Inhibitors of PTP1B / NCK1 interaction, methods for producing the same, and methods for using the same.

Abstract

The present invention generally relates to synthetic peptides that bind to NCK1. The present invention further relates to methods of using peptides to inhibit the interaction between NCK1 and PTP1B, and to treat diseases or disorders associated with insulin resistance, including type 2 diabetes and obesity. [Selected Figure] Figure 1A

Description

INHIBITORS OF PTP1B / NCK1 INTERACTION AND METHODS OF MAKING AND USING SAMECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 486,457, filed February 22, 2023, the entire disclosure of which is hereby incorporated by reference in its entirely for all purposes.SEQUENCE LISTING

[0002] This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on February 19, 2024, is named CGP-OOlWO SL.xml and is 252 kilobytes in size.FIELD OF THE DISCLOSURE

[0003] The disclosure relates generally to synthetic peptides which bind NCK1 and their use in treating diseases and disorders, including obesity and Type 2 Diabetes (T2D).BACKGROUND

[0004] Diabetes is a chronic metabolic disease involving the production and / or activity of insulin. It is estimated that more than 500 million people around the world are living with diabetes, and this number is expected to continue to increase. In the United States alone, 140 million adults have diabetes or prediabetes, mostly linked to excessive body weight and sedentary lifestyle. Type 2 diabetes (T2D; z.e., Type 2 diabetes mellitus) is the most common form of diabetes, accounting for approximately 90% of diabetes cases (Ong et al. (2023) LANCET 402(10397): 203-34). T2D is characterized by hyperglycemia resulting from insulin resistance. There is no approved cure for T2D, and treatment for the disease can require a lifetime of continuous medication. T2D is a progressive condition and thus, treatment typically must increase over time to keep blood glucose levels within the recommended range. Complications from T2D can have a considerable impact on health, resulting in damage to organs throughout the body. T2D is also a significant cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation. Only a limited number of approved medications for treatment of T2D exist, and most approaches focus on similar targeting systems, such as insulins, metformin, and glucagon like 1 peptide (GLP) analogues (e.g. semaglutide and liraglutide). However, current interventions are not always successful, can have significant side effects, and do not target the root cause of T2D, insulin resistance. Accordingly, there is a substantial need for novel, more effective treatments for T2D.

[0005] Obesity is a complex disease and a major risk factor not only for T2D (with 80% of T2D patients being overweight or obese), but also for other chronic illnesses and associated mortality, such as cardiovascular diseases (e.g., heart disease, stroke), hypertension, metabolic syndrome, atherosclerosis, non-alcoholic fatty liver disease (NAFLD), various forms of dementia, including Alzheimer's disease, cancer and other diseases (Lin et al. (2021) FRONT. ENDOCRINOL. 12: 706978). It is believed that the “Western diet” is fuelling an obesity epidemic, with rates of excess body fat accumulation and obesity growing fast in adults and children across all ages. In 2020, it was estimated that 38% of the world population is classified as overweight or obese. This is projected to rise to 51% by 2035, continuing a trajectory that saw worldwide obesity nearly triple between 1975-2016 (Lobstein et al., World Obesity Atlas 2023, World Obesity Federation). First-line treatment plans for obesity start with lifestyle intervention, including diet and physical activity, which are then supplemented with medications such as GLP-1 analogues, lipase inhibitors, and appetite suppressors. However, many of these medications are of limited efficacy and / or may cause significant adverse side effects, and so there is a significant unmet need for additional obesity treatments.

[0006] The insulin receptor (IR) is a transmembrane receptor tyrosine kinase (RTK) which binds extracellular ligands (e.g., insulin) and thereby initiates the phosphoinositide 3 -kinase (PI3K) / Protein Kinase B (Akt) signaling cascade in the IR signaling pathway, ultimately resulting in glucose uptake. Defects in IR signaling (e.g., decreased IR kinase activity, decreased cellular levels of IR, and / or decreased downstream pathway signaling from the IR) can contribute to a decrease in responsiveness to normal insulin levels, for example, insulin resistance, which is known to be a key factor in the development of T2D.

[0007] Protein-tyrosine phosphatase IB (PTP1B) is an endoplasmic reticulum (ER)-associated phosphatase. PTP1B is known to interact with, and dephosphorylate, the activated insulin receptor, thereby resulting in the downregulation of the insulin receptor signaling pathway (Bock et al. (2006) DIABETES 55(12): 3536-3549). In mice, genetic ablation of the gene encoding PTP1B is known to result in enhanced insulin sensitivity and increased insulin receptor phosphorylation (Tsou et al. (2013) FRONT. NEUROSCI. 6: 192). Additionally, PTP1B -I- mice are resistant to weight gain, and remain insulin-sensitive when placed on a high-fat diet (Elchebly et al. (1999) SCIENCE 283(5407): 1544-48). PTP1B is also a negative regulator of leptin receptor. Accordingly, PTP1B has been contemplated as a therapeutic target, particularly for the treatment of obesity and type 2 diabetes (Zabolotny et al. (2002) DEV. CELL 2(4): 489- 95). However, to date, no inhibitors of PTP1B have been approved in the United States or Europe for the treatment of T2D.

[0008] Accordingly, there is a need in the art for compositions and methods for treating diseases or disorders associated with insulin resistance (e.g., T2D, obesity, etc.), for example, by inhibiting certain activities of PTP1B in a subject in need thereof.SUMMARY OF THE INVENTION

[0009] The invention is based, in part, upon the discovery that Cellular Protein-tyrosine phosphatase IB (PTP1B) interacts with the SH3-2 domain of the non-catalytic region of tyrosine kinase 1 protein (NCK1) to produce a cellular signaling complex involved in the insulin receptor (IR) signaling pathway. NCK1 is a cytoplasmic adaptor protein known to be involved in transducing signals from receptor tyrosine kinases to downstream signaling recipients. NCK1 modulates the expression of PTP1B, and it has been observed that NCKl depletion enhances insulin sensitivity similar to that seen with PTP1B inhibition (Li et al. (2014) CELL COMMUN. SIGNAL. 12(1): 71).

[0010] As discussed herein, it has been found that the interaction between the SH3-2 domain of NCK1 and PTP1B can modulate the downstream signaling activity of the insulin receptor and the IR mediated pathway. By contacting NCK1 with an agent (e.g., a peptide) that interferes with the interaction between the NCK1 SH3-2 domain and PTP1B, PTP IB-mediated downregulation of the IR signaling pathway can be suppressed, thereby restoring IR signaling (see, FIGURES 1A-C). Additionally, it is contemplated that interfering with the specific complex formation between NCK1 and PTP1B (as opposed to inhibiting PTP1B activity broadly) will not suppress other activities of PTP IB, which are important for normal cellular function. Likewise, by only targeting one domain of NCK1, it is anticipated that other important functions of the NCK1 adaptor protein will not be materially impacted. Disruption of the NCK1-PTP1B complex presents a novel approach to functionally achieving selective inhibition ofPTPIB.

[0011] Accordingly, the disclosure provides, among other things, agents, e.g., synthetic peptides, that bind NCK1, and particularly the SH3-2 domain of NCK1. Furthermore, the NCK1 -binding synthetic peptides of the disclosure can be administered to a subject in need thereof to treat or prevent a disease or disorder, e.g, diabetes or obesity.

[0012] Accordingly, in a first aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of (i) from six to thirty or (ii) from six to fifty consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1PPX2R (SEQ ID NO: 1), wherein Xi and X2 are each independently any amino acid, and (a) the proline at position 1 of SEQ ID NO: 1is the N-terminal amino acid and is optionally modified by covalent linkage to a carbonylcontaining moiety; or (b) the N-terminal amino acid is acetylated and the C-terminal amino acid is ami dated.

[0013] In a second aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of six to thirty or six to fifty consecutive amino acids including an N- terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1PPX2R (SEQ ID NO: 1), wherein Xi and X2 are each independently any amino acid, and (a) the proline at position 1 of SEQ ID NO: 1 is the N- terminal amino acid and is optionally modified by covalent linkage to a carbonyl-containing moiety; (b) the N-terminal amino acid is chemically modified (e.g., acetylated) and / or the C- terminal amino acid is chemically modfied (e.g., amidated), or (c) the C-terminal amino acid is arginine provided that, (i) if X2 is arginine, then Xi is not arginine or glutamine, (ii) if X2 is serine, then Xi is not arginine, and (iii) if X2 is methionine, then Xi is not a histidine.

[0014] For each of the first and second aspects, in certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid (e.g., arginine, histidine, and lysine) or a negatively charged amino acid (e.g., glutamic acid). In certain embodiments, Xi is an uncharged amino acid, e.g., a hydrophobic amino acid. In certain embodiments Xi is an amino acid selected from the group consisting of alanine, asparagine, and serine. In certain embodiments of any of the foregoing aspects and embodiments, X2 is a charged amino acid, for example, a positively charged amino acid (e.g., arginine, histidine, or lysine) or a negatively charged amino acid (e.g., glutamic acid). In certain embodiments, X2 is an uncharged amino acid, for example, an amino acid selected from the group consisting of alanine, asparagine, cysteine, serine, and tryptophan. In certain embodiments, X2 is a hydrophobic amino acid, for example, an amino acid selected from the group consisting of alanine, cysteine, and tryptophan.

[0015] In each of the foregoing aspects, Xi is selected from (i) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine, (ii) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine or (iii) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. Alternatively or in addition, X2 is selected from (i) the groupconsisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, (ii) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, or (iii) the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0016] In a third aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of seven to ten consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is a non-aromatic amino acid; (3) if Xi is alanine and X2 is valine, then X3 is not proline; (4) if X2 is proline and X3 is arginine, then Xi is not arginine or glutamine; and (5) if X2 is proline and X3 is methionine, then Xi is not histidine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0017] In a related aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of seven to ten consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein Xi and X3 are each independently any amino acid and X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; provided that if (a) Xi is alanine and X2 is valine, then X3 is not proline; (b) X2 is proline and X3 is arginine, then Xi is not arginine or glutamine; and (c) X2 is proline and X3 is methionine, then Xi is not histidine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0018] In a fourth aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of eleven consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid, (2); X2 is a non-aromatic amino acid; (3) X-ds either absent or any amino acid; and (4) if X2 is proline and X4 is not absent, then (i) Xi is not threonine, (ii) X3 is not lysine, and / or (iii) X4 is not serine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0019] In a related aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of eleven consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi and X3 are each independently any amino acid, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and X4is either absent or any amino acid; provided that if X2 is proline and X4is not absent, then (i) Xi is not threonine; (ii) X3 is not lysine; and / or (iii) X4 is not serine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0020] In a fifth aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of twelve consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is a non-aromatic amino acid; (3) X4is either absent or any amino acid; and (4) if X2 is proline and X4is not absent, then (i) Xi is not arginine, (ii) X3 is not threonine, and / or (iii) X4 is not threonine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N- terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0021] In a related aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of twelve consecutive amino acids including an N-terminal amino acidand a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi and X3 are each independently any amino acid; X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and X-ds either absent or any amino acid; provided that if X2 is proline and X4is not absent, then (i) Xi is not arginine; (ii) X3 is not threonine; and / or (iii) X4 is not threonine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0022] In a sixth aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of thirteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is a non-aromatic amino acid; and (3) X4is either absent or any amino acid. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0023] In a related aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of thirteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi and X3 are each independently any amino acid; X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and X4is either absent or any amino acid. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0024] In a seventh aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of fourteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is a non-aromatic amino acid; (3) Xus either absent or any amino acid; (4) if Xi is alanine and X2 is valine, then X3 is not proline; and (5) if X2 is proline and Xus absent, then (i) Xi is not arginine, and / or (ii) X3 is not serine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N- terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonylcontaining moiety).

[0025] In a related aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of fourteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi and X3 are each independently any amino acid; X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; X4is either absent or any amino acid, provided that, if Xi is alanine and X2 is valine, then X3 is not proline; and if X2 is proline and X4is absent, then: (i) Xi is not arginine; and / or (ii) X3 is not serine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonylcontaining moiety).

[0026] In an eighth aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of fifteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is a non-aromatic amino acid; (3) X4is either absent or any amino acid; and (4) if X2 is proline and X4is not absent, then (i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4is not the C-terminal amino acid; (ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and (iii) if X4 is proline, then (a) if Xi is methionine, then X3 is not asparagine; and (b) if Xi is arginine, then X3 is not glycine. In certain embodiments, if theproline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0027] In a nineth aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of fifteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is a non-aromatic amino acid; (3) Xus either absent or any amino acid; and (4) if X2 is proline and Xus not absent, then: (i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4 is not the C-terminal amino acid and / or the N-terminal amino acid is not a proline; (ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and (iii) if X4 is proline, then: (a) if Xi is methionine, then X3 is not asparagine; and (b) if Xi is arginine, then X3 is not glycine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0028] In a related aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of fifteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi and X3 are each independently any amino acid; X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; X4is either absent or any amino acid; provided that if X2 is proline and X4is not absent, then: (i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4is not the C-terminal amino acid and / or the N-terminal amino acid is not a proline; (ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and (iii) if X4 is proline, then: (a) if Xi is methionine, then X3 is not asparagine; and (b) if Xi is arginine, then X3 is not glycine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0029] In a tenth aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of (i) sixteen to thirty (including intervening integers) or (ii) sixteen to fifty (including intervening integers), consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is a non-aromatic amino acid; (3) Xus either absent or any amino acid; and (4) wherein, if the synthetic peptide consists essentially of twenty consecutive amino acids, then the four most C-terminal amino acid residues of the synthetic peptide is not SLSR (SEQ ID NO: 85). In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0030] In a related aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of (i) sixteen to thirty or (ii) sixteen to 50, consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi and X3 are each independently any amino acid; X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and X4is either absent or any amino acid; and wherein, if the synthetic peptide consists essentially of twenty consecutive amino acids, then the four most C-terminal amino acid residues of the synthetic peptide is not SLSR (SEQ ID NO: 85). In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0031] In certain embodiments of the fifth to tenth aspects, Xi is a charged amino acid, for example, a positively charged amino acid (e.g., arginine, histidine, or lysine) or a negatively charged amino acid (e.g., glutamic acid). In certain embodiments, Xi is an uncharged amino acid, for example, a hydrophobic amino acid. In certain embodiments, Xi is selected from the group consisting of alanine, asparagine, and serine. Alternatively or in addition, in certain embodiments, X2 is an uncharged, non-aromatic amino acid, for example, alanine or proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid, e.g., alanine. In certain embodiments, X2 is a charged amino acid, e.g., a positively charged amino acid, e.g., arginine.Alternatively or in addition, in certain embodiments, X3 is a charged amino acid, for example, a positively charged amino acid (e.g., arginine, histidine, or lysine) or a negatively charged amino acid (e.g., glutamic acid). In certain embodiments, X3 is an uncharged amino acid, for example, an amino acid selected from the group consisting of alanine, asparagine, cysteine, serine, and tryptophan. In certain embodiments, X3 is a hydrophobic amino acid, for example, an amino acid selected from the group consisting of alanine, cysteine, and tryptophan.

[0032] In certain embodiments of the sixth to tenth aspects, X4is a charged amino acid, e.g., a positively charged amino acid (e.g., arginine, histidine, and lysine). In certain embodiments, X4 is a negatively charged amino acid (e.g., aspartic acid or glutamic acid). In certain embodiments, X4is an uncharged amino acid (e.g., alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In certain embodiments, X4is an aliphatic amino acid (e.g., alanine, glycine, isoleucine, leucine, proline, or valine). In certain embodiments, X4is an aromatic amino acid (e.g., phenylalanine, tryptophan, or tyrosine). In certain embodiments, X4is a sulfur-containing amino acid (e.g., cysteine or methionine. In certain embodiments, X4is an amino acid with a hydroxyl-containing side chain (e.g., serine or threonine). In certain embodiments, X4is an acidic amino acid (e.g., aspartic acid or glutamic acid). In certain embodiments, X4is a basic amino acid (e.g., arginine, histidine, or lysine). In certain embodiments, X4is an amino acid with an amide-containing sidechain (e.g., asparagine or glutamine).

[0033] In certain embodiments of the fifth to tenth aspects, Xi is selected from the group consisting of (i) alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine, (ii) alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine, or (iii) alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine. Alternatively, or in addition, X2is selected from the group consisting of (i) alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine or (ii) alanine, isoleucine, proline, and valine, or isoleucine, proline, and valine. Alternatively or in addition, X3 is selected from the group consisting of (i) alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, (ii) alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, or (iii) alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0034] In an eleventh aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of from (i) six to thirty or (ii) six to fifty, consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PRPPKRXi (SEQ ID NO: 4), wherein: (1) Xi is absent or any amino acid, and (2) if Xi is isoleucine and the synthetic peptide is a 15-mer, then Xi is not the C-terminal amino acid, and optionally proline is not the N-terminal amino acid. In certain embodiments, if the proline at position 1 of SEQ ID NO: 4 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0035] In certain embodiments of the eleventh aspect, Xi is a charged amino acid, such as a positively charged amino acid (e.g., arginine, histidine, or lysine) or a negatively charged amino acid (e.g., aspartic acid or glutamic acid). In certain embodiments, Xi is an uncharged amino acid (e.g., alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine). In certain embodiments, Xi is an aliphatic amino acid (e.g., alanine, glycine, isoleucine, leucine, proline, or valine). In certain embodiments, the synthetic peptide comprises the amino acid sequence of PRPPKRI (SEQ ID NO: 5), PRPPKRIL (SEQ ID NO: 6), or PRPPKRILE (SEQ ID NO: 7). In certain embodiments, Xi is an aromatic amino acid (e.g., phenylalanine, tryptophan, or tyrosine). In certain embodiments, Xi is a sulfur-containing amino acid (e.g., cysteine or methionine). In certain embodiments, Xi is an amino acid with a hydroxyl-containing side chain (e.g., serine or threonine. In certain embodiments, Xi is an acidic amino acid (e.g., aspartic acid or glutamic acid). In certain embodiments, Xi is a basic amino acid (e.g, arginine, histidine, or lysine). In certain embodiments, Xi is an amino acid with an amide-containing sidechain (e.g, asparagine or glutamine). In certain embodiments, the synthetic peptide has the amino acid sequence of PRPPKR (SEQ ID NO: 8), PPRPPKR (SEQ ID NO: 9) or PPPEHIPPPPRPPKR (SEQ ID NO: 10).

[0036] In certain embodiments of aspects 1 through 11, the foregoing synthetic peptides exhibit binding to the SH3-2 domain of NCK1 with a Koof < 1,000 pM, for example, as determined by isothermal titration calorimetry (ITC). In certain embodiments, the foregoing synthetic peptides exhibit binding to the SH3-2 domain of NCK1 with a KD of < 600 pM, for example, asdetermined by ITC. In certain embodiments, the foregoing synthetic peptides exhibit binding to the SH3-2 domain of NCK1 with a KD of < 300 pM, for example, as determined by ITC.

[0037] In a twelfth aspect, the disclosure provides a synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty, consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein Xi and X3 are each independently any amino acid; X2 is selected from the group consisting of selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a KD of < 1,000 pM, for example, as determined by ITC. In certain embodiments, the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a KD of < 600 pM or less < 300 pM, for example, as determined by ITC. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine. It is contemplated that the synthetic peptide consists essentially of an amino acid sequence of at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen consecutive amino acids. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N- terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0038] In certain embodiments of any of the foregoing peptides, at least one, two or more amino acids are covalently linked to a chemical moiety not present in a natural amino acid. For example, it is contemplated that the N-terminal amino acid can be chemically modified, for example, the N-terminal amino acid can comprise a chemical modification not present in a naturally occuring amino acid. For example, in certain embodiments, the N-terminal amino acid is acetylated. In certain embodiments, the N-terminal amino acid is H-pyroglutamic acid (H- Pyr). Alternatively or in addition, it is contemplated that the C-terminal amino acid can be chemically modified, for example, the C-terminal amino acid can comprise a chemical modification not present in a naturally occuring amino acid. For example, in certain embodiments, the C-terminal amino acid is amidated. In certain embodiments, the C-terminal amino acid comprises an ethylamide (NHEt) group.

[0039] In certain embodiments, the synthetic peptide optionally comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 1, 2, 3, or 4. The amino acid residue at position Xo can be selected from (i) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, or (ii) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0040] It is contemplated that the synthetic peptides disclosed herein can be provided in a composition containing a salt, for example, an acetate salt (e.g., bis-acetate or tri-acetate).

[0041] In a related aspect, the disclosure provides a pharmaceutical composition comprising any one of the foregoing synthetic peptides or a salt thereof (e.g., an acetate salt), and a pharmaceutically acceptable carrier.

[0042] In a related aspect, the disclosure provides a pharmaceutical composition comprising a synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty, consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine; X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonylcontaining moiety).

[0043] In certain embodiments, Xi is selected from (i) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine or (ii) alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, andvaline. Alternatively or in addition to each of the foregoing, X2 is selected from (i) the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine, (ii) the group consisting of alanine, isoleucine, proline, and valine or (iii) the group consisting of isoleucine, proline, and valine. Alternatively or in addition to each of the foregoing, X3 is selected from (i) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine or (ii) the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0044] The pharmaceutical composition is sterile, is can be provided as a dried composition (e.g., freeze dried or lyophilized) or as an aqueous composition (e.g., the peptide solubilized in water for injection or suitable buffer) such as an aqueous composition suitable for injection. The concentration of the synthetic peptide in the aqueous composition can be between about 150 mg / mL and about 400 mg / mL, or between about 200 mg / mL and about 300 mg / mL. Depending upon the mode of delivery, the disclosure provides a delivery system comprising (i) delivery device (e.g., a syringe such as a prefilled syringe) and (ii) a composition comprising any one or more of the peptides disclosed herein or a pharmaceutical composition disclosed herein.

[0045] In another aspect, the disclosure provides a method of modulating the activity of NCK1, the method comprising contacting NCK1 with an agent that disrupts an interaction between PTP1B and NCK1 thereby to modulate the activity of NCK1. Exemplary agents include, for example, a protein (e.g., antibody or antigen binding fragment thereof) or peptide (e.g., a peptide disclosed herein), that disrupts the interaction between PTP1B and NCK1 via the SH3-2 domain of NCK1. The contacting step disrupts the interaction between PTP1B and NCK1. In certain embodiments, the step of contacting results in modulating the activity of PTP1B.

[0046] In another aspect, the disclosure provides a method of modulating the activity of NCK1, the method comprising contacting NCK1 with any one of the foregoing synthetic peptides or pharmaceutical compositions, thereby to modulate the activity of NCK1. In certain embodiments, the step of contacting disrupts the interaction between PTP1B and NCK1. In certain embodiments, the step of contacting results in modulating the activity of PTP1B.

[0047] In another aspect, the disclosure provides a method of decreasing body fat mass in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide described herein or a pharmaceutical composition comprising a syntheticpeptide disclosed herein and a pharmaceutically acceptable carrier, thereby to decrease body fat mass of the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) or (ii) six to fifty, consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein: (1) Xi and X3 are each independently any amino acid; and (2) X2 is a non-aromatic amino acid. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N- terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonylcontaining moiety).

[0048] In a related aspect, the disclosure provides a method of decreasing body fat mass in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide described herein or a pharmaceutical composition comprising a synthetic peptide disclosed herein and a pharmaceutically acceptable carrier, thereby to decrease body fat mass of the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty, consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein: (1) Xi and X3 are each independently any amino acid; and (2) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., covalent linkage to a carbonyl-containing moiety).

[0049] In a related aspect, the disclosure provides a method of decreasing body fat mass in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the foregoing synthetic peptides or pharmaceutical compositions, thereby to decrease body fat mass of the subject.

[0050] In another aspect, the disclosure provides a method of treating obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat obesity in the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty, consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ IDNO: 2), wherein: (1) Xi and X3 are each independently any amino acid; and (2) X2 is a nonaromatic amino acid. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0051] In a related aspect, the disclosure provides a method of treating obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat obesity in the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty, consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein: (1) Xi and X3 are each independently any amino acid; and (2) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0052] In a related aspect, the disclosure provides a method of treating obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the foregoing synthetic peptides or pharmaceutical compositions, thereby to treat obesity in the subject.

[0053] In another aspect, the disclosure provides a method of treating or preventing diabetes (e.g., Type 2 diabetes) in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide described herein or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat or prevent diabetes in the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein (1) Xi and X3 are each independently any amino acid; and (2) X2 is a non-aromatic amino acid. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0054] In a related aspect, the disclosure provides a method of treating or preventing diabetes (e.g., Type 2 diabetes) in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat or prevent diabetes in the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein (1) Xi and X3 are each independently any amino acid; and (2) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine. In certain embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0055] In a related aspect, the disclosure provides a method of treating or preventing diabetes (e.g., Type 2 diabetes) in a subject in need thereof, the method comprising administering to the subject any one of the foregoing synthetic peptides or pharmaceutical compositions, thereby to treat or prevent diabetes in the subject.

[0056] In certain embodiments of the foregoing methods, the subject is a mammal, e.g., a human. In each of the foregoing methods, the administration comprises systemic administration (e.g, via subcutaneous administration).

[0057] In each of the foregoing methods, in certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid (e.g., arginine, histidine, or lysine) or a negatively charged amino acid (e.g., glutamic acid). In certain embodiments, Xi is an uncharged amino acid, for example, a hydrophobic amino acid. In certain embodiments, Xi is selected from the group consisting of alanine, asparagine, and serine. Alternatively or in addition, in certain embodiments of the foregoing methods, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is a hydrophobic, non- aromatic amino acid, e.g., alanine. In certain embodiments, X2 is a charged amino acid, e.g., a positively charged amino acid, e.g. arginine. Alternatively or in addition to each of the foregoing methods, X3 is a charged amino acid, for example, a positively charged amino acid (e.g, arginine, histidine, or lysine) or a negatively charged amino acid (e.g, glutamic acid). In certain embodiments, X3 is an uncharged amino acid, for example, an amino acid selected from the group consisting of alanine, asparagine, cysteine, serine, and tryptophan. In certainembodiments, X3 is a hydrophobic amino acid, for example, an amino acid selected from the group consisting of alanine, cysteine, and tryptophan.

[0058] These and other aspects and features of the invention are described in the following detailed description and claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The invention can be more completely understood with reference to the following drawings, in which:

[0060] FIGURE 1A is a schematic that depicts interaction between PTP1B (labeled “2”) and NCK1 (labeled “1”) (upper panel) and disruption between the two proteins using a NCK1- binding modulating agent (labeled “3”), such as a synthetic peptide disclosed herein (lower panel). FIGURES 1B-1C are schematics depicting the impact of NCK1 and PTP1B on insulin receptor signaling (FIGURE IB), and the how the use of a NCK1 -binding modulating agent can disrupt the interaction between NCK1 and PTP1B and consequently enhance insulin pathway signaling, thereby restoring insulin sensitivity (FIGURE 1C). The term “IR” represents insulin receptor, the term “IRSl” represents insulin receptor substrate 1, and the term “PI3K / AKT” represents “phosphoinositide 3-kinase / protein kinase B.”

[0061] FIGURES 2A-2D depict immunoblots showing co-immunoprecipitation of FLAG- PTP1B and HA-NCK1 in HEK-293 cells co-transfected with both proteins. Either FLAG- PTP1B (FIGURE 2A) or HA-NCK1 (FIGURE 2B) was immunoprecipitated from the cotransfected cells, and Western blotting was used to detect the presence of the other fusion protein in the cell lysate (lane 2) and the IP eluate (lane 4). Non-transfected HEK-293 cells were used as negative controls (lanes 1 and 3). Ponceau staining was used to measure total protein in the FLAG-PTP1B IP assay (FIGURE 2C) and in the HA-NCK1 IP assay (FIGURE 2D).

[0062] FIGURE 3 depicts an immunoblot showing co-immunoprecipitation of His-PTPIB and GST-tagged full-length NCK1 (“N” or “GST NCK1”) or GST-tagged SH3-2 domain of NCK1 (“SH3-2” or “GST SH3-2”). Bead-bound GST fusion protein was co-incubated with the indicated concentration of His-PTPIB, and His-PTPIB was detected in the IP eluate by Western blotting (top image). GST alone (“X” or “Control GST”) and GST-tagged PTP1B (“P” or “GST PTP1B”) were used as negative controls. “E protein” refers to the purified SH3-2 domain of NCK1. Ponceau staining was used to measure total protein (bottom image).

[0063] FIGURE 4A depicts an immunoblot showing that certain peptides prevent coimmunoprecipitation of FLAG-PTP1B and GST-tagged SH3-2 domain of NCK1 (“SH3”). GST was fused to full-length NCK1 (“Nckl”), all SH3 domains of NCK1 (“SH3”), the NCK1 SH2 domain (“SH2”), the NCKl SH3-1 domain (“SH3 1”), the NCKl SH3-2 domain (“SH3 2”), and the NCK1 SH3-3 domain (“SH3 3”). GST alone was used as a negative control (“GST”). FLAG-PTP1B was incubated with the indicated bead-bound GST-fusion protein, and FLAG- PTP1B was detected in the IP eluate by western blotting. The outlined region in column “SH3- 2” identifies the PTP1B band. For GST-SH3-2 and FLAG-PTP1B, the mixture was further incubated with one of peptides A through K, (1 mM). FIGURE 4B depicts an input control for the immunoblot. FIGURE 4C depicts a Ponceau stain for the immunoblot, which was used to measure total protein. FIGURE 4D depicts a legend summarizing the peptides tested in columns A through K, and summarizes which peptides did and did not break the interaction between FLAG-PTP1B and SH3-2, based on the results in FIGURE 4A.

[0064] FIGURE 5 is a bar graph showing the efflux ratios of different compounds in a Caco-2 assay. The efflux ratio of MD20 (0.252) is indicated as a bolded line.

[0065] FIGURE 6 is a graph showing MD20 concentrations in the indicated tissues in a mouse following intraperitoneal (IP) administration of the peptide at a dose of 30 mg / kg. Tissue samples were collected at 0, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-injection. MD20 was not detected in liver tissue at any time point.

[0066] FIGURES 7A-7B are graphs showing body weight changes in mice following daily IP injection of MD17 or MD20 at a dose of 15 mg / kg or 30 mg / kg for 28 consecutive days. Mice injected with a PBS solution were used as a control. Results are reported as mean body weight of the treatment group at weekly timepoints (FIGURE 7A) and as the percentage change in body weight at the conclusion of the 4-week protocol (FIGURE 7B).

[0067] FIGURES 8A-8D are bar graphs showing changes in lean mass and fat mass (as measured by Echo MRI scan) in mice following daily IP injection of MD17 or MD20 at a dose of 15 mg / kg or 30 mg / kg for 28 consecutive days. Mice injected with a PBS solution were used as a control. Results are reported as mean lean mass (FIGURE 8A) and mean fat mass (FIGURE 8B) pre- and post-treatment, and as the percentage change in lean mass (FIGURE 8C) and fat mass (FIGURE 8D) at the conclusion of the 4-week protocol. Data represent mean ± SEM; statistical differences were determined using one-way ANOVA with Bonferroni post hoc tests.

[0068] FIGURES 9A-9F are bar graphs showing metabolic markers and liver toxicity markers in mice following daily IP injection of MD17 or MD20 at a dose of 15 mg / kg or 30 mg / kg for 28 consecutive days. Mice injected with a PBS solution were used as a control. Mice were fasted for 5 hours at the conclusion of the experiment, and blood and serum samples were analyzed for blood glucose (FIGURE 9A), insulin (FIGURE 9B), leptin (FIGURE 9C), free fatty acid (FAA, FIGURE 9D), and for liver toxicity markers alanine aminotransferase (ALT) (FIGURE 9E) and aspartate aminotransferase (AST) (FIGURE 9F). Data represent mean ± SEM; statistical differences were determined using one-way ANOVA with Bonferroni post hoc tests.

[0069] FIGURE 10 depicts a diagram summarizing the mouse high-fat diet (HFD) study described in Example 7, which was used to investigate the effect of daily IP MD20 administration (30 mg / kg) on a mouse model of obesity and type 2 diabetes.

[0070] FIGURES 11A-11B are graphs showing body weight changes in HFD-fed mice following daily administration of MD20. After eight weeks of HFD feeding, mice were administered a daily IP injection of MD20 (30 mg / kg) or a vehicle control for 7 weeks. Results are reported as mean body weight of the treatment group at weekly timepoints (FIGURE 11 A) and as the percentage change in body weight at weekly timepoints post-treatment with MD20 (FIGURE 11B)

[0071] FIGURES 12A-12F are graphs showing changes in lean mass and fat mass (as measured by Echo MRI scan) in HFD-fed mice following daily administration of MD20. After eight weeks of HFD feeding, mice were administered a daily IP injection of MD20 (30 mg / kg) or a vehicle control for 7 weeks. Results for the indicated weeks post-treatment are reported as mean fat mass (FIGURE 12A, FIGURE 12B), mean lean mass (FIGURE 12A, FIGURE 12D), and percentage change in fat mass (FIGURE 12C). Results at the conclusion of the protocol are reported as percentage change in fat mass (FIGURE 12E) and the percentage change in lean mass (FIGURE 12F). Data represent mean ± SEM; statistical differences were determined using repeated measures two-way ANOVA followed by a Bonferroni post hoc test or two-tailed student’s t-test.

[0072] FIGURES 13A-13B are graphs showing the results of an insulin tolerance test (ITT) in HFD-fed mice following 7 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. At the conclusion of the study, mice were 5-hour fasted and subsequently injected IP with 0.6 mU / g insulin. Blood glucose levels were measured at 0, 15, 30, 60, and 90 minutes post-insulin injection. Results were reported as blood glucose concentration (FIGURE 13A) and as percentage change in blood glucose levels (FIGURE 13B). Data represent mean ± SEM;statistical differences were determined using repeated measures two-way ANOVA followed by Bonferroni post hoc test.

[0073] FIGURE 14 is a bar graph showing changes in blood glucose levels in HFD-fed mice before and during the course of 7 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. Blood glucose levels were measured prior to starting an HFD diet (“pre-HFD”), following administration of an HFD diet but prior to treatment (“pre-treat”), and at the indicated timepoints following daily treatment with MD20 or vehicle control (“week #”). Data represent mean ± SEM; statistical differences were determined using one-way ANOVA followed by Bonferroni post hoc test.

[0074] FIGURE 15 is a graph showing the results of an glucose tolerance test (GTT) in HFD- fed mice following 7 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. At the conclusion of the study, mice were 5-hour fasted and subsequently injected IP with 2 mg / g glucose. Blood glucose levels were measured at 0, 15, 30, 60, and 90 minutes post-glucose injection. Results were reported as blood glucose concentration. Data represent mean ± SEM; statistical differences were determined using repeated measures two-way ANOVA followed by Bonferroni post hoc test.

[0075] FIGURES 16A-16F are graphs showing serum levels of various markers in HFD-fed mice following 7 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. Mice were fasted for 5 hours at the conclusion of the experiment, and serum samples were analyzed for levels of insulin (FIGURE 16A), leptin (FIGURE 16B), cholesterol (FIGURE 16C), free fatty acids (FIGURE 16D), triglycerides (FIGURE 16E), and liver triglycerides (FIGURE 16F) Data represent mean ± SEM; statistical differences were determined using two tailed student’ s t-test.

[0076] FIGURES 17A-17B are graphs showing serum ALT and AST activity in HFD-fed mice following 7 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. Mice were fasted for 5 hours at the conclusion of the experiment, and serum samples were analyzed for alanine aminotransferase (ALT) activity (FIGURE 17A) and aspartate aminotransferase (AST) activity (FIGURE 17B). Data represent mean ± SEM; statistical differences were determined using two tailed student’s t-test.

[0077] FIGURES 18A-18B are graphs showing changes in body weight in db / db mice following daily subcutaneous (SC) administration of either 15, 30, or 45 mg / kg MD18 (FIGURE 18A) or 15, 30, or 45 mg / kg MD20 (FIGURE 18B) for the indicated number of days, as compared to a vehicle control (“PBS”). Data represent means ± SEM.

[0078] FIGURES 19A-19D are graphs showing changes in changes in fat mass (FIGURE 19A and FIGURE 19C) and lean mass (FIGURE 19B and FIGURE 19D) in db / db mice following daily SC administration of MD18 (15, 30, or 45 mg / kg), MD20 (15, 30, or 45 mg / kg), or a vehicle control for 41 days. Data are presented as absolute mass (FIGURE 19A and FIGURE 19B) and as percent change in mass pre- versus post-treatment (FIGURE 19C and FIGURE 19D) Data represent means ± SEM.

[0079] FIGURES 20A-20E are graphs showing the results of a glucose tolerance test (GTT) in db / db mice. A GTT was carried after 4 weeks of daily SC administration of either MD18 (15, 30, or 45 mg / kg;), MD20 (15, 30, or 45 mg / kg;), or a vehicle control, as indicated. The GTT was carried out by IP injecting 5h-fasted mice with glucose. Blood glucose levels were measured pre-glucose-inj ection and at 15, 30, 60, and 90 minutes post-glucose injection, and results were reported as blood glucose concentration (FIGURE 20A and FIGURE 20B), as percent change in blood glucose concentration pre- versus post-treatment (FIGURE 20C and FIGURE 20D), and as the glucose area under the curve (AUC; FIGURE 20E). Data represent means ± SEM.

[0080] FIGURES 21A-21C are graphs showing the results of an insulin tolerance test (ITT) in db / db mice following 6 weeks of daily SC administration of either MD18 (15, 30, or 45 mg / kg; FIGURE 21A), MD20 (15, 30, or 45 mg / kg; FIGURE 21B), or a vehicle control. The ITT was carried out by injecting 5h-fasted mice IP with 1 lU / kg insulin. Blood glucose levels were measured pre-insulin-injection and at 15, 30, 60, and 90 minutes post-insulin injection. Results were reported as percentage change in glucose levels (FIGURES 21A-21B) and as the glucose AUC (FIGURE 21C). Data represent means ± SEM.

[0081] FIGURES 22A-22E are bar graphs showing basal blood glucose levels in db / db mice over after 1 week (FIGURE 22A), 2 weeks (FIGURE 22B), 3 weeks (FIGURE 22C), 4 weeks (FIGURE 22D), or five weeks (FIGURE 22E) of daily SC administration of either MD18 (15, 30, or 45 mg / kg), MD20 (15, 30, or 45 mg / kg), or a vehicle control (“PBS”). Blood glucose was measured using AlphaTRAK 2 glucose strips and glucometer (Abbott, UK) or by glucose assay (AB65333, Abeam), as indicated. Data represent means ± SEM.

[0082] FIGURES 23A-23B are graphs showing serum levels of insulin (FIGURE 23A) and leptin (FIGURE 23B) in 5-hour-fasted db / db mice following about 6 weeks of daily SC administration of MD18 (15, 30, or 45 mg / kg), MD20 (15, 30, or 45 mg / kg), or a vehicle control (“PBS”). Data represent mean ± SEM.

[0083] FIGURES 24A-24C are graphs showing body weight changes in LDLR- / - mice following daily administration of MD20. After eight weeks of HFD feeding, mice were administered a daily IP injection of MD20 (30 mg / kg) or a vehicle control for 6 weeks. Results are reported as mean body weight at weekly timepoints post-HFD-feeding (FIGURE 24A) or post-MD20 treatment (FIGURE 24C), or as percentage change in body weight post-treatment (FIGURE 24B) Data represent mean ± SEM; statistical differences were determined using two way ANOVA followed by Bonferroni post hoc tests.

[0084] FIGURES 25A-25F are graphs showing changes in lean mass and fat mass (as measured by Echo MRI scan) in HFD-fed LDLR- / - mice following daily administration of MD20 (30 mg / kg) or a vehicle control for 6 weeks. Data were recorded at the indicated timepoints post-treatment, and results are reported as absolute fat mass (FIGURE 25A), percentage change in fat mass (FIGURES 25B and FIGURE 25C), absolute lean mass (FIGURE 25D), and percentage change in lean mass (FIGURES 25E and FIGURE 25F). Data represent mean ± SEM; statistical differences were determined using repeated measures two-way ANOVA followed by a Bonferroni post hoc test or two-tailed student’ s t-test.

[0085] FIGURES 26A-26D are graphs showing the results of an insulin tolerance test (ITT) in HFD-fed LDLR- / - mice following 6 weeks of daily IP administration of either MD20 (30 mg / kg) or a vehicle control. At the conclusion of the study, mice were 5h-fasted and subsequently injected IP with 0.6 mU / g insulin. Blood glucose levels were measured pre-insulin injection (basal glucose concentration; FIGURE 26C) and at 15, 30, 60, and 90 minutes postinsulin injection. Results were reported as blood glucose concentration (FIGURE 26A), as percentage change in glucose levels (FIGURE 26B), and as the glucose AUC FIGURE 26D). Data represent mean ± SEM; statistical differences were determined using (repeated measures two-way ANOVA followed by Bonferroni post hoc test.

[0086] FIGURES 27A-27C are graphs showing the results of a glucose tolerance test (GTT) in HFD-fed LDLR- / - mice. A GTT was carried after 0 weeks (FIGURE 27A), 3 weeks (FIGURE 27B), and 5 weeks (FIGURE 27C) of daily IP administration of either MD20 (30 mg / kg) or a vehicle control. The GTT was carried out by IP injecting 5h-fasted mice with 2 mg / g glucose. Blood glucose levels were measured at 0, 15, 30, 60, and 90 minutes post-glucose injection, and results were reported as blood glucose concentration. Data represent mean ± SEM; statistical differences were determined using repeated measures two-way (FIGURES 27A-27B) or one-way (FIGURE 27C) ANOVA followed by Bonferroni post hoc test.

[0087] FIGURES 28A-28F are graphs showing levels of various hormones, lipids, and hepatic toxicity markers in HFD-fed LDLR- / - mice following 6 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. Mice were fasted for 5 hours at the conclusion of the experiment, and serum samples were analyzed for levels of insulin (FIGURE 28A), leptin (FIGURE 28B), cholesterol (FIGURE 28C), free fatty acids (FIGURE 28D), triglycerides (FIGURE 28E), alanine aminotransferase (ALT) activity (FIGURE 28G), and aspartate aminotransferase (AST) activity (FIGURE 28H). Liver triglyceride levels were also analyzed (FIGURE 28F) Data represent mean ± SEM; statistical differences were determined using two tailed student’ s t-test.

[0088] FIGURES 29A-29B summarize the extent of aortic plaque coverage in HFD-fed LDLR- / - mice following 6 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. FIGURE 29A is a graph showing percentage of aortic plaque coverage in MD20- treated mice (“Treatment”) as compared to control mice (“Vehicle”). Data represent mean ± SEM; statistical differences were determined using one- or two-tailed student’s t-test. FIGURE 29B is a photograph depicting a mouse aorta stained with Sudan IV to measure plaque coverage.

[0089] FIGURES 30A-30E are graphs showing expression of various genes in tissues of HFD-fed LDLR- / - mice following 6 weeks of daily IP administration of MD20 (30 mg / kg) or a vehicle control. Mice were fasted for 5 hours at the conclusion of the experiment, liver and white adipose tissue (“WAT”) samples were collected, and gene expression was measured by qRT-PCR. Expression of glucose transporter 4 (GLUT4; FIGURE 30A) and stearoyl-CoA- desaturase 1 (SCD1; FIGURE 30B) was measured in adipose tissue, and expression of Glucose- 6-phosphatase (G6P; FIGURE 30C), Activating Transcription Factor 4 (ATF4; FIGURE 30D), and 3 -hydroxy-3 -methylglutaryl (HMGCS; FIGURE 30E) was measured in liver tissue. Data represent mean ± SEM; statistical differences were determined using two tailed student’s t-test.DETAILED DESCRIPTION

[0090] The invention is based, in part, upon the discovery that PTP1B interacts with the SH3-2 domain of the protein NCK1 to produce an intracellular signaling complex involved in the insulin receptor signaling pathway. NCK1 is a cytoplasmic adaptor protein known to be involved in transducing signals from receptor tyrosine kinases to downstream signaling recipients. NCK1 modulates the expression of PTP1B, and NCKl depletion enhances insulin sensitivity similar to that seen with PTP1B inhibition (Li et al. (2014) supra). Deletion of NCK1 has previously been found to decrease ER stress, improve glucose tolerance and insulin signaling in mice (Latreille et al. (2011) AM. J. PHYSIOL. ENDOCRINOL. METAB. 300(3): E423-E434;Bywaters et al. (2021)) and to increase pancreatic P cells survival and insulin synthesis under diabetic conditions (Yamani et al. (2014) MOL. BIO . CELL 25(5): 702-711; Yamani et al. (2015) CELL. SIGNAL. 27(12): 2555-2567). NCK1 has been found to play a role in regulating insulin signaling via activation of the PI3K / AKT pathway via a PTP IB-dependent mechanism, i.e. forming an interaction complex with PTP1B (Li et al. (2014) supra).

[0091] As discussed herein, it has been found that the interaction between the SH3-2 domain of NCK1 and PTP1B can modulate the activity of the insulin receptor (IR) and the IR-mediated pathway. By contacting NCK1 with an agent that interferes with the interaction between the NCK1 SH3-2 domain and PTP1B, PTP IB-mediated downregulation of the IR signaling pathway can be suppressed, thereby restoring IR signaling (see, FIGURES 1A-1C). Additionally, it is anticipated that interfering with the specific complex formation between NCK1 and PTP1B (as opposed to inhibiting PTP IB activity broadly) will not suppress other activities of PTP IB, which are important for normal cellular function. Likewise, by only targeting one domain of NCK1, it is anticipated that other important functions of the NCK1 adaptor protein will not be materially impacted. Disruption of the NCK1-PTP1B complex presents a novel approach to functionally achieving selective inhibition of PTP IB.

[0092] Accordingly, the disclosure provides, among other things, synthetic peptides that bind NCK1, and particularly the SH3-2 domain of NCK1. Furthermore, the NCKl-binding synthetic peptides of the disclosure can be administered to a subject in need thereof to treat or prevent a disease or disorder, e.g., diabetes or obesity.I. Definitions

[0093] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0094] The term “effective amount” as used herein refers to the amount of an active agent (e.g., a synthetic peptide) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route. For example, an effective amount may be an amount sufficient to achieve one or more of the following: (i) modulate an activity of NCK1, (ii) modulate an activity of PTP1B, (iii) inhibit, disrupt, reduce, or prevent NCKl-binding to PTP IB, (iv) increase, enhance, or restore insulin receptor signaling; (v) treat or prevent a disease or disorder, e.g., Type 2 diabetes or obesity, or a symptom or manifestationthereof; (vi) decrease body weight or lessen an increase in body weight; or (vii) decrease body fat mass or lessen an increase in body fat mass.

[0095] As used herein, the term “isolated” when used in conjunction with a particular article (e.g., protein, peptide, nucleic acid, or cell) is understood to mean: (1) that the article has been separated or purified from other components (e.g., other proteins, peptides, nucleic acids, cells, or cellular materials) and / or chemicals (e.g., reagents used in manufacture); (2) that the article may be separated or purified from the environment in which it may exist in nature, for example, a tissue or fluid sample; or (3) that the article does not occur in nature. For example, a molecule that is removed from a cell that produces it, is “isolated.” A chemically synthesized molecule is “isolated.” As used herein, the term “isolated” can also refer to a molecule that is substantially free of other molecules of the same species. For example, a protein or peptide may be “isolated” from other proteins or peptides having different amino acid sequences. The purity or homogeneity of a desired article can be assayed using techniques well known in the art, including gel electrophoresis, high performance liquid chromatography, or mass spectrometry. Any of the polynucleotides or polypeptides described herein may be isolated.

[0096] As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0097] The term “pharmaceutically acceptable carrier” as used herein refers to buffers, carriers, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers include any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see e.g. Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23d ed. 2020).

[0098] As used herein, “percent identity” between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Similarly,percent “identity” between a nucleic acid sequence and a reference sequence is defined as the percentage of nucleotides in the nucleic acid sequence that are identical to the nucleotides in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent sequence identity (e.g., nucleic acid sequence identity or amino acid sequence identity) can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST (Basic Local Alignment Search Tool), BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. For a discussion of basic issues in searching sequence databases see Altschul et al., (1994) NATURE GENETICS 6: 119-129, which is fully incorporated by reference herein. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0099] As used herein, “treat”, “treating”, and “treatment” refer to the treatment of a disease, disorder, or symptom or manifestation of such in a subject, e.g., in a human. This includes: (a) preventing a disease or disorder, (b) inhibiting the disease, disorder, etc., i.e., slowing or arresting its progress or development; and (b) relieving the disease, disorder, etc., i.e., causing regression of the disease state. As used herein, “prevent”, “preventing” and “prevention” refer to causing a disease, disorder, or symptom or manifestation of such not to occur for at least a period of time in at least some subjects. As used herein, the terms “subject” and “patient” refer to an organism to be treated by the methods and compositions described herein. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably includes humans.

[0100] As used herein, the term “polypeptide”, refers to a polymer of amino acids, optionally including one or more amino acid analogs. A protein is a molecule composed of one or more polypeptides. A peptide is a relatively short polypeptide, typically between about 2 and 60 amino acids in length. However, depending upon the circumstances, the terms “protein”, “polypeptide”, and “peptide” may be used interchangeably. It is contemplated that polypeptides used herein may contain amino acids such as those that are naturally found in proteins, or can be replaced with amino acids that are not naturally found in proteins and / or amino acid analogs that are not amino acids, but where the resulting polypeptides have comparable binding activity or other biological activities as the polypeptides disclosed herein. As used herein, an “analog” of an amino acid may be a different amino acid that structurally resembles the amino acid or a compound other than an amino acid that structurally resembles the amino acid. A large number of art-recognized analogs of the 20 amino acids commonly found in proteins (the “standard”amino acids) are known. One or more of the amino acids in a polypeptide may be modified, for example, by the addition of a chemical entity such as an amide group or an acetyl group. For example, the polypeptide may be acetylated, e.g., at the N-terminus and / or amidated, e.g., at the C -terminus.

[0101] Polypeptides may, for example, be purified from natural sources, produced in vitro or in vivo using recombinant DNA technology in suitable expression systems (e.g., by recombinant host cells or in transgenic animals or plants), synthesized through chemical means such as solid phase peptide synthesis, liquid-phase peptide synthesis, and / or methods involving chemical ligation of synthesized peptides (see, e.g., Kent (2003) J PEPT. SCE 9(9):574-93), or any combination of the foregoing. These methods are well known, and one of skill in the art will be able to select and implement an appropriate method for synthesizing the peptides and polypeptides described herein.

[0102] As used herein, the terms “polypeptide sequence” or “amino acid sequence” can refer to a sequence of covalently coupled amino acids, but is not necessarily restricted to the sequence information (z.e. the succession of letters or three letter codes chosen among the letters and codes used as abbreviations for amino acid names) that biochemically characterizes a polypeptide. A polypeptide sequence presented herein is presented in an N-terminal to C-terminal direction unless otherwise indicated.

[0103] The term “purified”, as used herein, means that an entity or substance is separated from one or more other entities or substances with which it was previously found before being purified. An entity or substance may be partially purified, substantially purified, or pure. A substance or entity such as a nucleic acid or polypeptide is considered pure when it is removed from substantially all other compounds or entities other than a solvent and any ions contained in the solvent, z.e., it constitutes at least about 90%, more preferably at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99% of the dry weight of the composition. A partially or substantially purified compound or entity such as a nucleic acid or polypeptide may be removed from at least 50%, at least 60%, at least 70%, or at least 80% by weight of the material with which it is naturally found, e.g, cellular material such as cellular proteins and / or nucleic acids. In certain embodiments, the purified nucleic acid or polypeptide constitutes at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or even more, by dry weight, of the total nucleic acid or polypeptide, respectively, in a composition. Methods for assessing purity are known in the art and include chromatographic methods, immunologicalmethods, electrophoretic methods, etc. Any of the polynucleotides or polypeptides described herein may be purified.

[0104] As used herein, “recombinant host cells”, “host cells”, and other such terms, denote prokaryotic or eukaryotic cells or cell lines that have been used as recipients for an exogenous nucleic acid (typically DNA) such as an expression vector into which a nucleic acid portion that encodes a polypeptide of interest has been inserted. These terms include the progeny of the original cell into which the vector or other nucleic acid has been introduced. Appropriate unicellular host cells include any of those routinely used in expressing polynucleotides (e.g, eukaryotic, mammalian, and / or viral polynucleotides) including, for example, prokaryotes, such as E. coli; and eukaryotes, including for example, fungi, such as yeast (e.g., Pichia pastoris and Saccharomyces cerevisiaey, insect cells (e.g., Sf9), plant cells, and animal cells, e.g., mammalian cells such as CHO, Rl.l, B-W, L-M, African Green Monkey Kidney cells (e.g COS-1, COS-7, BSC-1, BSC-40 and BMT-10) and cultured human cells. Terms such as “host cells”, etc., are also used to refer to cells or cell lines that can be used as recipients for an exogenous nucleic acid, prior to its introduction. As used herein, the term “recombinant nucleic acid” refers to a nucleic acid that contains nucleic acid portions that are not found joined together in nature. As used herein, the term “recombinant polypeptide” refers to a polypeptide that is produced by transcription and translation of an exogenous nucleic acid by a recombinant host cell, typically after introduction of an expression vector that contains a portion that encodes the recombinant polypeptide into the host cell.

[0105] As used herein, the term “charged amino acid” refers to an amino acid selected from arginine, histidine, lysine, aspartic acid (i.e., aspartate), and glutamic acid (i.e., glutamate). As used herein, the term “positively charged amino acid” refers to an amino acid selected from arginine, histidine, and lysine. As used herein, the term “negatively charged amino acid” refers to an amino acid selected from aspartic acid (i.e., aspartate) and glutamic acid (i.e., glutamate).

[0106] As used herein, the term “uncharged amino acid” refers to an amino acid selected from alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0107] As used herein, the term “hydrophobic amino acid” refers to an amino acid selected from alanine, cysteine, isoleucine, leucine, methionine, phenylalanine, tryptophan, and valine.

[0108] As used herein, the term “hydrophilic amino acid” refers to an amino acid selected from arginine, asparagine, aspartic acid, glutamine, glutamic acid, and lysine.

[0109] As used herein, the term “neutral amino acid” refers to an amino acid selected from glycine, histidine, proline, serine, threonine, and tyrosine.

[0110] As used herein, the term “aliphatic amino acid” refers to an amino acid selected from alanine, glycine, isoleucine, leucine, proline, and valine.

[0111] As used herein, the term “aromatic amino acid” refers to an amino acid selected from phenylalanine, tryptophan, and tyrosine. As used herein, the term “non-aromatic amino acid” refers to an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, and valine.

[0112] As used herein, the term “conservative substitution” refers to a substitution with a structurally similar amino acid. For example, conservative substitutions may include those within the following groups: Ser and Cys; Leu, He, and Vai; Glu and Asp; Lys and Arg; Phe, Tyr, and Trp; and Gin, Asn, Glu, Asp, and His. Conservative substitutions may also be defined by the BLAST (Basic Local Alignment Search Tool) algorithm, the BLOSUM substitution matrix (e.g., BLOSUM 62 matrix), or the PAM substitution^ matrix (e.g, the PAM 250 matrix). In certain embodiments, a synthetic peptide of the disclosure comprises 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 conservative substitutions relative to a “wild type” or reference peptide or amino acid sequence. In certain embodiments, a synthetic peptide of the disclosure comprises less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, less than 13, less than 14, or less than 15 conservative substitutions relative to a “wild type” or reference peptide or amino acid sequence.

[0113] As used herein, the term "carbonyl-containing moiety” refers to any chemical moiety that contains a carbonyl group. In certain embodiments, the carbonyl-containing moiety is not and does not contain an amino acid. A non-limiting example of a carbonyl-containing moiety is an acetyl group. In certain embodiments, the carbonyl group of the carbonylcontaining moiety is covalently attached to the most N-terminal nitrogen of the N-terminal amino acid in a peptide. In certain embodiments, if the N-terminal amino acid is proline, then the carbonyl group of the carbonyl-containing moiety is covalently attached to the nitrogen adjacent to the alpha carbon in proline’s five-membered ring.11. Synthetic Peptides

[0114] The present disclosure encompasses the finding that synthetic peptides comprising a motif of PTP1B can bind NCK1. NCK1 is a cytoplasmic adaptor protein known to be involved in transducing signals from receptor tyrosine kinases to downstream signaling proteins. NCK1comprises, in the N- to C-terminal direction, a first, second, and third SRC Homology 3 domain (SH3 domain; referred to herein as SH3-1, SH3-2, and SH3-3, respectively) and an SRC Homology 2 domain (SH2 domain). SH3 domains are small, intracellular protein domains which mediate protein-protein interactions. An exemplary amino acid sequence for wild-type human NCK1 is set forth as SEQ ID NO: 140. The SH3-1, SH3-2, and SH3-3 domains of NCK1 correspond to positions 2-61, 106-165, and 190-252, respectively, of SEQ ID NO: 140.

[0115] Without wishing to be bound by theory, it is believed that by binding to the SH3-2 domain of NCK1, the synthetic peptides comprising at least a portion of the PTP1B motif reduce, inhibit, or prevent interaction between PTP1B and NCK1, thereby specifically modulating the activity of PTP1B, e.g., by reducing or inhibiting PTP IB-mediated downregulation of insulin receptor signaling and / or by modulating regulation of the PI3K / AKT pathway.

[0116] Accordingly, in one aspect, the disclosure provides a synthetic NCKl-binding peptide. In certain embodiments, a synthetic NCKl-binding peptide of the disclosure comprises the amino acid sequence of SEQ ID NO: 1 :PX1PPX2R (SEQ ID NO: 1), wherein Xi and X2 are each independently any amino acid. In certain embodiments, the peptide is 5 to 60 (e.g., 6 to 60), e.g., 5 to 50 (e.g., 6 to 50), e.g., 5 to 40 (e.g., 6 to 40) or 5 to 30 (e.g., 6 to 30), 5 to 20 (e.g, 6 to 20) or 5 to 10 (e.g., 6 to 10) consecutive amino acids in length. In certain embodiments, the peptide is 5 to 100 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100), 15 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 consecutive amino acids in length.

[0117] In certain embodiments, Xi is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, Xi is a charged amino acid. In certain embodiments, Xi a positively charged amino acid. For example, in certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is a negatively charged amino acid. For example, in certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. For example, in certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is selected from the group consisting of alanine, asparagine, and serine.

[0118] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0119] In certain embodiments, X2 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, X2 is a charged amino acid. In certain embodiments, X2 is a positively charged amino acid. For example, in certain embodiments, X2 is arginine, histidine, or lysine. In certain embodiments, X2 is lysine. In certain embodiments, X2 is a negatively charged amino acid. For example, in certain embodiments, X2 is glutamic acid. In certain embodiments, X2 is an uncharged amino acid. For example, in certain embodiments, X2 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X2 is a hydrophobic amino acid. For example, in certain embodiments, X2 is alanine, cysteine, or tryptophan.

[0120] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0121] In certain embodiments, Xi and X2 are both charged amino acids. In certain embodiments, Xi and X2 are both positively charged amino acids. In certain embodiments, Xi is arginine and X2 is lysine.

[0122] In certain embodiments, the proline in position 1 in SEQ ID NO: 1 is the N-terminal amino acid of the synthetic peptide. In certain embodiments, the proline in position 1 is N-terminally modified by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety. Without wishing to be bound by theory, the linkage to a carbonyl-containing moiety may enhance binding of the synthetic peptide to NCK1.

[0123] In certain embodiments, the proline in position 1 in SEQ ID NO: 1 is not the N- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) to the N-terminus of the proline in position 1. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is, independently, any amino acid. In certain embodiments, the amino acid immediately N-terminal to position 1 is proline. In certain embodiments, the two amino acids immediately N-terminal to position 1 are both proline. In certain embodiments, the three amino acids immediately N- terminal to position 1 are all proline. In certain embodiments, the amino acids immediately N- terminal to position 1 are, in the N-to-C terminal direction: Pro-Pro-Glu-His-Ile-Pro-Pro-Pro (SEQ ID NO: 85).

[0124] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 1. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0125] In certain embodiments, the arginine in position 6 in SEQ ID NO: 1 is the C-terminal amino acid of the synthetic peptide. In certain embodiments, the arginine in position 6 is modified. In certain embodiments, the arginine in position 6 is the C-terminal amino acid of the synthetic peptide, and comprises an amide moiety at the C-terminus.

[0126] In certain embodiments, the arginine in position 6 in SEQ ID NO: 1 is not the C- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) to the C-terminus of the arginine in position 6. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is,independently, any amino acid. In certain embodiments, the amino acid immediately C-terminal to position 6 is isoleucine. In certain embodiments, the two amino acids immediately C-terminal to position 6 are, in the N-to-C-terminal direction, isoleucine and leucine. In certain embodiments, the three amino acids immediately C-terminal to position 6 are, in the N-to-C- terminal direction, isoleucine, leucine, and glutamic acid.

[0127] In certain embodiments, the N-terminal amino acid is chemically modified (e.g., acetylated) and / or the C-terminal amino acid is chemically modified (e.g., amidated).

[0128] In certain embodiments, the N-terminal amino acid is acetylated and the C-terminal amino acid is amidated.

[0129] In certain embodiments, a synthetic NCKl-binding peptide of the disclosure comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2), wherein Xi, X2, and X3 are each independently any amino acid. In certain embodiments, X2 is a non-aromatic amino acid. In certain embodiments, the peptide is 5 to 60 (e.g., 6 to 60), e.g., 5 to 50 (e.g., 6 to 50), e.g., 5 to 40 (e.g., 6 to 40) or 5 to 30 (e.g., 6 to 30), 5 to 20 (e.g., 6 to 20) or 5 to 10 (e.g., 6 to 10) consecutive amino acids in length. In certain embodiments, the peptide is 5 to 100 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100), 15 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 consecutive amino acids in length.

[0130] In certain embodiments, Xi is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, Xi is a charged amino acid. In certain embodiments, Xi a positively charged amino acid. For example, in certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is a negatively charged amino acid. For example, in certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. For example, in certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is selected from the group consisting of alanine, asparagine, and serine.

[0131] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, andvaline. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0132] In certain embodiments, X2 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, or an aromatic amino acid. In certain embodiments, X2 is an uncharged amino acid. In certain embodiments, X2 is an uncharged, non-aromatic amino acid. For example, in certain embodiments, X2 is proline or alanine. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic amino acid. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid, e.g., alanine. In certain embodiments, X2 is a charged amino acid. In certain embodiments, X2 is a positively charged amino acid, e.g., arginine.

[0133] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0134] In certain embodiments, X3 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, X3 is a charged amino acid. In certain embodiments, X3 is a positively charged amino acid. For example, in certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is a negatively charged amino acid. For example, in certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. For example, in certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. For example, in certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0135] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0136] In certain embodiments, Xi is arginine, X2 is proline, and / or X3 is lysine.

[0137] In certain embodiments, if Xi is alanine and X2 is valine, then X3 is not proline. In certain embodiments, if X2 is proline and X3 is arginine, then Xi is not arginine or glutamine. In certain embodiments, if X2 is proline and X3 is methionine, then Xi is not histidine.

[0138] In certain embodiments, the proline in position 1 in SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide. In certain embodiments, the proline in position 1 is N- terminally modified by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety.

[0139] In certain embodiments, the proline in position 1 in SEQ ID NO: 2 is not the N- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) to the N-terminus of the proline in position 1. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is, independently, any amino acid. In certain embodiments, the amino acid immediately N-terminal to position 1 is proline. In certain embodiments, the two amino acids immediately N-terminal to position 1 are both proline. In certain embodiments, the three amino acids immediately N- terminal to position 1 are all proline. In certain embodiments, the amino acids immediately N- terminal to position 1 are, in the N-to-C terminal direction: Pro-Pro-Glu-His-Ile-Pro-Pro-Pro (SEQ ID NO: 85).

[0140] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 2. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0141] In certain embodiments, the arginine in position 6 in SEQ ID NO: 2 is the C-terminal amino acid of the synthetic peptide. In certain embodiments, the arginine in position 6 ismodified. In certain embodiments, the arginine in position 6 is the C-terminal amino acid and comprises an amide moiety at the C-terminus.

[0142] In certain embodiments, the arginine in position 6 in SEQ ID NO: 2 is not the C- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) to the C-terminus of the arginine in position 6. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is, independently, any amino acid. In certain embodiments, the amino acid immediately C-terminal to position 6 is isoleucine. In certain embodiments, the two amino acids immediately C-terminal to position 6 are, in the N-to-C-terminal direction, isoleucine and leucine. In certain embodiments, the three amino acids immediately C-terminal to position 6 are, in the N-to-C- terminal direction, isoleucine, leucine, and glutamic acid.

[0143] In certain embodiments, a synthetic NCKl-binding peptide of the disclosure comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi, X2, and X3, are each independently any amino acid, and wherein X4 is either absent or any amino acid. In certain embodiments, X2 is a non-aromatic amino acid. In certain embodiments, the peptide is 5 to 60 (e.g., 6 to 60), e.g., 5 to 50 (e.g., 6 to 50), e.g., 5 to 40 (e.g., 6 to 40) or 5 to 30 (e.g., 6 to 30), 5 to 20 (e.g., 6 to 20) or 5 to 10 (e.g., 6 to 10) consecutive amino acids in length. In certain embodiments, the peptide is 5 to 100 (e.g., 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100), 15 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 consecutive amino acids in length.

[0144] In certain embodiments, Xi is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, Xi is a charged amino acid. In certain embodiments, Xi a positively charged amino acid. For example, in certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is a negatively charged amino acid. For example, in certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. Forexample, in certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is selected from the group consisting of alanine, asparagine, and serine.

[0145] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0146] In certain embodiments, X2 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, or a non-aromatic amino acid. In certain embodiments, X2 is an uncharged amino acid. In certain embodiments, X2 is an uncharged, non-aromatic amino acid, e.g., proline or alanine. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic amino acid. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid, e.g., alanine. In certain embodiments, X2 is a charged amino acid. In certain embodiments, X2 is a positively charged amino acid, e.g., arginine.

[0147] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0148] In certain embodiments, X3 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, X3 is a charged amino acid. In certain embodiments, X3 is a positively charged amino acid. For example, in certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is a negatively charged amino acid. For example, in certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. For example, in certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. For example, in certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0149] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0150] In certain embodiments, X4 is absent. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, X4 is an uncharged amino acid. In certain embodiments, X4 is a hydrophobic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide- containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0151] In certain embodiments, Xi is arginine, X2 is proline, X3 is lysine, and / or X4 is absent.

[0152] In certain embodiments wherein X2 is proline and X s not absent: (i) Xi is not threonine; (ii) X3 is not lysine; and / or (iii) X4 is not serine. In certain embodiments wherein X2 is proline and X4 is not absent: (i) Xi is not arginine; (ii) X3 is not threonine; and / or (iii) X4 is not threonine. In certain embodiments wherein Xi is alanine and X2 is valine, X3 is not proline. In certain embodiments wherein X2 is proline and X4 is absent, (i) Xi is not arginine and / or X3 is not serine. In certain embodiments wherein X2 is proline and X4 is not absent: (i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4 is not the C-terminal amino acid; (ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and / or (iii) if X4 is proline, then: (a) if Xi is methionine, then X3 is not asparagine; and (b) if Xi is arginine, then X3 is not glycine.

[0153] In certain embodiments, the proline in position 1 in SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide. In certain embodiments, the proline in position 1 is N- terminally modified by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety.

[0154] In certain embodiments, the proline in position 1 in SEQ ID NO: 3 is not the N- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) to the N-terminus of the proline in position 1. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is, independently, any amino acid. In certain embodiments, the amino acid immediately N-terminal to position 1 is proline. In certain embodiments, the two amino acids immediately N-terminal to position 1 are both proline. In certain embodiments, the three amino acids immediately N- terminal to position 1 are all proline. In certain embodiments, the amino acids immediately N- terminal to position 1 are, in the N-to-C terminal direction: Pro-Pro-Glu-His-Ile-Pro-Pro-Pro (SEQ ID NO: 85).

[0155] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0156] In certain embodiments, the arginine in position 6 in SEQ ID NO: 3 is the C-terminal amino acid of the synthetic peptide. In certain embodiments, the arginine in position 6 is modified. In certain embodiments, the arginine in position 6 is the C-terminal amino acid and comprises an amide moiety at the C-terminus.

[0157] In certain embodiments wherein X4 is present, X4 in SEQ ID NO: 3 is the C-terminal amino acid of the synthetic peptide. In certain embodiments, X4 is modified. In certain embodiments, X4 is the C-terminal amino acid and comprises an amide moiety at the C- terminus.

[0158] In certain embodiments wherein X4 is present, X4 in SEQ ID NO: 3 is not the C- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) C-terminally to X4. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is, independently, any amino acid. In certain embodiments, the amino acid immediately C-terminal to X4 is leucine. In certain embodiments, the two amino acids immediately C-terminal to X4 are, in the N-to-C-terminal direction, leucine and glutamic acid.

[0159] In certain embodiments, a synthetic NCKl-binding peptide of the disclosure comprises the amino acid sequence of SEQ ID NO: 4:PRPPKRXi (SEQ ID NO: 4) wherein Xi is either absent or any amino acid. In certain embodiments, the peptide is 5 to 60 (e.g., 6 to 60), e.g., 5 to 50 (e.g., 6 to 50), c.g, 5 to 40 (e.g., 6 to 40) or 5 to 30 (e.g., 6 to 30), 5 to 20 (e.g., 6 to 20) or 5 to 10 (e.g., 6 to 10) consecutive amino acids in length. In certain embodiments, the peptide is 5 to 100 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100), 15 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 consecutive amino acids in length.

[0160] In certain embodiments, Xi is absent. In certain embodiments, Xi is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, a neutral amino acid, an aliphatic amino acid, an aromatic amino acid, or a non-aromatic amino acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi in SEQ ID NO: 4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, andlysine. In certain embodiments, Xi is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, Xi is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xi is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, Xi is isoleucine. In certain embodiments, Xi is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, Xi is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, Xi is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, Xi is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, Xi is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, Xi is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0161] In certain embodiments wherein Xi is isoleucine, Xi is not the C-terminal amino acid.

[0162] In certain embodiments, the proline in position 1 in SEQ ID NO: 4 is the N-terminal amino acid of the synthetic peptide. In certain embodiments, the proline in position 1 is N- terminally modified by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety.

[0163] In certain embodiments, the proline in position 1 in SEQ ID NO: 4 is not the N- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) to the N-terminus of the proline in position 1. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is, independently, any amino acid. In certain embodiments, the amino acid immediately N-terminal to position 1 is proline. In certain embodiments, the two amino acids immediately N-terminal to position 1 are both proline. In certain embodiments, the three amino acids immediately N- terminal to position 1 are all proline. In certain embodiments, the amino acids immediately N- terminal to position 1 are, in the N-to-C terminal direction: Pro-Pro-Glu-His-Ile-Pro-Pro-Pro (SEQ ID NO: 85).

[0164] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 4. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0165] In certain embodiments wherein Xi is absent, the arginine in position 6 in SEQ ID NO: 4 is the C-terminal amino acid of the synthetic peptide. In certain embodiments, the arginine in position 6 is modified. In certain embodiments, the arginine in position 6 is the C-terminal peptide and comprises an amide moiety at the C-terminus.

[0166] In certain embodiments wherein Xi is present, Xi in SEQ ID NO: 4 is the C-terminal amino acid of the synthetic peptide. In certain embodiments, Xi is modified. In certain embodiments, Xi is the C-terminal peptide and comprises an amide moiety at the C-terminus.

[0167] In certain embodiments wherein Xi is present, Xi in SEQ ID NO: 4 is not the C- terminal amino acid of the synthetic peptide. For example, in certain embodiments, the synthetic peptide comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or more additional consecutive amino acids covalently linked (e.g., linked by peptide bond) to C-terminally to Xi. In certain embodiments, each of the at least 1, at least 2, at least 3, etc., additional consecutive amino acids is, independently, any amino acid. In certain embodiments, the amino acid immediately C-terminal to Xi is leucine. In certain embodiments, the two amino acids immediately C-terminal to Xi are, in the N-to-C-terminal direction, leucine and glutamic acid.

[0168] In certain embodiments, a synthetic peptide of the disclosure comprises the amino acid sequence of a NCKl-binding fragment of PTP1B. For example, in certain embodiments, the synthetic peptide comprises, consists essentially of, or consists of, the amino acid sequence of any one of SEQ ID NOs: 5-21, 135-137, or 141-143. In certain embodiments, the synthetic peptide comprises, consists essentially of, or consists of, the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the synthetic peptide comprises, consists essentially of, or consists of, the amino acid sequence of SEQ ID NO: 9. In certain embodiments, the synthetic peptide comprises, consists essentially of, or consists of, the amino acid sequence of SEQ ID NO: 10.Table 1. Exemplary NCKl-binding fragments of PTP1B

[0169] In certain embodiments, a synthetic peptide of the disclosure comprises, consists essentially of, or consists of, the amino acid sequence of any of SEQ ID NOs: 1-4, and the amino acid sequence of the synthetic peptide is at least 50% identical to the amino acid sequence of any one of SEQ ID NOs: 5-21, 135-137, or 141-143. For example, in certain embodiments, the amino acid sequence of the synthetic peptide is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90 %, or at least 95% identical to the amino acid sequences of any one of SEQ ID NOs: 5-21, 135-137, or 141-143. In certain embodiments, the synthetic peptide comprises the amino acid sequence of any of SEQ IDNOs 1-4, and the amino acid sequence of the synthetic peptide is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90 %, or at least 95% identical to the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the synthetic peptide comprises the amino acid sequence of any of SEQ ID NOs 1-4, and the amino acid sequence of the synthetic peptide is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90 %, or at least 95% identical to the amino acid sequence of SEQ ID NO: 9. In certain embodiments, the synthetic peptide comprises the amino acid sequence of any of SEQ ID NOs 1-4, and the amino acid sequence of the synthetic peptide is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90 %, or at least 95% identical to the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the synthetic peptide comprises a conservative substitution relative to any of the amino acid sequences of SEQ ID NOs: 5-21, 135- 137, or 141-143, e.g, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. In certain embodiments, the synthetic peptide comprises less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, or less than 13 conservative substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 5-21, 135-137, or 141-143, e.g., SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. In certain embodiments, the synthetic peptide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more conservative substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 5-21, 135-137, or 141-143, e.g., SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

[0170] In certain embodiments, a synthetic peptide of the disclosure comprises, or consists essentially of, or consists of the amino acid sequence of any one of SEQ ID NOs: 5-30, 32-33, 35, 38, 41, 59, 61-83, 87-89, 98, 100-137, 141-158, or 168. In certain embodiments, a synthetic peptide of the disclosure comprises, consists essentially of, or consists of the amino acid sequence of any one of the peptides set forth in Table 2.Table 2, Exemplary NCKl-binding peptides

[0171] In certain embodiments, a synthetic peptide of the disclosure comprises, consists essentially of, or consists of, the amino acid sequence of any of SEQ ID NOs: 1-4, and the amino acid sequence of the synthetic peptide is at least 50% identical to the amino acid sequence of any one of SEQ ID NOs: 5-30, 32-33, 35, 38, 41, 59, 61-83, 87-89, 98, 100-137, 141-158, or 168.For example, in certain embodiments, the amino acid sequence of the synthetic peptide is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90 %, or at least 95% identical to the amino acid sequences of any one of SEQ ID NOs: 5-30, 32-33, 35, 38, 41, 59, 61-83, 87-89, 98, 100-137, 141-158, or 168. In certain embodiments, the synthetic peptide comprises a conservative substitution relative to any of the amino acid sequences of SEQ ID NOs: 5-30, 32-33, 35, 38, 41, 59, 61-83, 87-89, 98, 100-137, 141-158, or 168. In certain embodiments, the synthetic peptide comprises less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, or less than 13 conservative substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 5-30, 32-33, 35, 38, 41, 59, 61-83, 87-89, 98, 100-137, 141-158, or 168. In certain embodiments, the synthetic peptide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more conservative substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 5-30, 32-33, 35, 38, 41, 59, 61-83, 87-89, 98, 100-137, 141-158, or 168.

[0172] In certain embodiments, a synthetic peptide of the disclosure comprises at least 3 proline residues. For example, in certain embodiments, the synthetic peptide comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 9, or at least 10 proline residues. In certain embodiments, the synthetic peptide has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 proline residues.

[0173] In certain embodiments, a synthetic peptide of the disclosure comprises at least 2 positively charged amino acids. For example, in certain embodiments, a synthetic peptide of the disclosure comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, atleast 9, or at least 10 positively charged amino acids. In certain embodiments, the synthetic peptide has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 positively charged amino acid residues.

[0174] In certain embodiments, it is contemplated that a synthetic peptide of the disclosure can consist essentially of (or consist of) 5 to 100 (e.g, 6 to 100), 5 to 95 (e.g., 6 to 95), 5 to 90 (e.g. 6 to 90), 5 to 85 (e.g., 6 to 85), 5 to 80 (e.g., 6 to 80), 5 to 75 (e.g., 6 to 75), 5 to 70 (e.g., 6 to 70), 5 to 65 (e.g., 6 to 65), 5 to 60 (e.g., 6 to 60), e.g., 5 to 50 (e.g., 6 to 50), e.g., 5 to 40 (e.g., 6 to 40) or 5 to 30 (e.g., 6 to 30), 5 to 20 (e.g., 6 to 20) or 5 to 10 (e.g., 6 to 10) consecutive amino acids. For example, in certain embodiments, the synthetic peptide consists essentially of (or consists of) 5 to 100, 5 to 95, 5 to 90, 5 to 85, 5 to 80, 5 to 75, 5 to 70, 5 to 65, 5 to 60, 5 to 55, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 19, 5 to 18, 5 to 17, 5 to 16, 5 to 15,5 to 14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 6 to 100, 6 to 95, 6 to 90, 6 to 85, 6 to 80, 6 to 75, 6 to 70, 6 to 65, 6 to 60, 6 to 55, 6 to 50, 6 to 45, 6 to 40, 6 to 35, 6 to 30, 6 to 25,6 to 20, 6 to 19, 6 to 18, 6 to 17, 6 to 16, 6 to 15, 6 to 14, 6 to 13, 6 to 12, 6 to 11, 6 to 10, 6 to 9,6 to 8, 6 to 7, 7 to 100, 7 to 95, 7 to 90, 7 to 85, 7 to 80, 7 to 75, 7 to 70, 7 to 65, 7 to 60, 7 to 55,7 to 50, 7 to 45, 7 to 40, 7 to 35, 7 to 30, 7 to 25, 7 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 7 to 14, 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 7 to 8, 8 to 100, 8 to 95, 8 to 90, 8 to 85, 8 to 80, 8 to 75, 8 to 70, 8 to 65, 8 to 60, 8 to 55, 8 to 50, 8 to 45, 8 to 40, 8 to 35, 8 to 30, 8 to 25, 8 to 20, 8 to 19, 8 to 18, 8 to 17, 8 to 16, 8 to 15, 8 to 14, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 100, 9 to 95, 9 to 90, 9 to 85, 9 to 80, 9 to 75, 9 to 70, 9 to 65, 9 to 60, 9 to 55, 9 to 50, 9 to 45,9 to 40, 9 to 35, 9 to 30, 9 to 25, 9 to 20, 9 to 19, 9 to 18, 9 to 17, 9 to 16, 9 to 15, 9 to 14, 9 to13, 9 to 12, 9 to 11, 9 to 10, 10 to 100, 10 to 95, 10 to 90, 10 to 85, 10 to 80, 10 to 75, 10 to 70,10 to 65, 10 to 60, 10 to 55, 10 to 50, 10 to 45, 10 to 40, 10 to 35, 10 to 30, 10 to 25, 10 to 20, 10 to 19, 10 to 18, 10 to 17, 10 to 16, 10 to 15, 10 to 14, 10 to 13, 10 to 12, 10 to 11, 11 to 100, 11 to 95, 11 to 90, 11 to 85, 11 to 80, 11 to 75, 11 to 70, 11 to 65, 11 to 60, 11 to 55, 11 to 50, 11 to45, 11 to 40, 11 to 35, 11 to 30, 11 to 25, 11 to 20, 11 to 19, 11 to 18, 11 to 17, 11 to 16, 11 to15, 11 to 14, 11 to 13, 11 to 12, 12 to 100, 12 to 95, 12 to 90, 12 to 85, 12 to 80, 12 to 75, 12 to 70, 12 to 65, 12 to 60, 12 to 55, 12 to 50, 12 to 45, 12 to 40, 12 to 35, 12 to 30, 12 to 25, 12 to20, 12 to 19, 12 to 18, 12 to 17, 12 to 16, 12 to 15, 12 to 14, 12 to 13, 13 to 100, 13 to 95, 13 to90, 13 to 85, 13 to 80, 13 to 75, 13 to 70, 13 to 65, 13 to 60, 13 to 55, 13 to 50, 13 to 45, 13 to40, 13 to 35, 13 to 30, 13 to 25, 13 to 20, 13 to 19, 13 to 18, 13 to 17, 13 to 16, 13 to 15, 13 to14, 14 to 100, 14 to 95, 14 to 90, 14 to 85, 14 to 80, 14 to 75, 14 to 70, 14 to 65, 14 to 60, 14 to55, 14 to 50, 14 to 45, 14 to 40, 14 to 35, 14 to 30, 14 to 25, 14 to 20, 14 to 19, 14 to 18, 14 to17, 14 to 16, 14 to 15, 15 to 100, 15 to 95, 15 to 90, 15 to 85, 15 to 80, 15 to 75, 15 to 70, 15 to65, 15 to 60, 15 to 55, 15 to 50, 15 to 45, 15 to 40, 15 to 3515 to 30, 15 to 25, 15 to 20, 15 to 19,15 to 18, 15 to 17, 15 to 16, 16 to 100, 16 to 95, 16 to 90, 16 to 85, 16 to 80, 16 to 75, 16 to 70,16 to 65, 16 to 60, 16 to 55, 16 to 50, 16 to 45, 16 to 40, 16 to 35, 16 to 30, 16 to 25, 16 to 20, 16 to 19, 16 to 18, 16 to 17, 17 to 100, 17 to 95, 17 to 90, 17 to 85, 17 to 80, 17 to 75, 17 to 70, 17 to 65, 17 to 60, 17 to 55, 17 to 50, 17 to 45, 17 to 40, 17 to 35, 17 to 30, 17 to 25, 17 to 20, 17 to 19, 17 to 18, 18 to 100, 18 to 95, 18 to 90, 18 to 85, 18 to 80, 18 to 75, 18 to 70, 18 to 65, 18 to 60, 18 to 55, 18 to 50, 18 to 45, 18 to 40, 18 to 35, 18 to 30, 18 to 25, 18 to 20, 18 to 19, 19 to 100, 19 to 95, 19 to 90, 19 to 85, 19 to 80, 19 to 75, 19 to 70, 19 to 65, 19 to 60, 19 to 55, 19 to 50, 19 to 45, 19 to 40, 19 to 35, 19 to 30, 19 to 25, 19 to 20, 20 to 100, 20 to 95, 20 to 90, 20 to 85, 20 to 80, 20 to 75, 20 to 70, 20 to 65, 20 to 60, 20 to 55, 20 to 50, 20 to 45, 20 to 40, 20 to 35, 20 to 30, 20 to 25, 25 to 100, 25 to 95, 25 to 90, 25 to 85, 25 to 80, 25 to 75, 25 to 70, 25 to 65, 25 to 60, 25 to 55, 25 to 50, 25 to 45, 25 to 40, 25 to 35, 25 to 30, 30 to 100, 30 to 95, 30 to 90, 30 to 85, 30 to 80, 30 to 75, 30 to 70, 30 to 65, 30 to 60, 30 to 55, 30 to 50, 30 to 45, 30 to 40, 30 to 35, 35 to 100, 35 to 95, 35 to 90, 35 to 85, 35 to 80, 35 to 75, 35 to 70, 35 to 65, 35 to 60, 35 to 55, 35 to 50, 35 to 45, 35 to 40, 40 to 100, 40 to 95, 40 to 90, 40 to 85, 40 to 80, 40 to 75, 40 to 70, 40 to 65, 40 to 60, 40 to 55, 40 to 50, 40 to 45, 45 to 100, 45 to 95, 45 to 90, 45 to85, 45 to 80, 45 to 75, 45 to 70, 45 to 65, 45 to 60, 45 to 55, 45 to 50, 50 to 100, 50 to 95, 50 to90, 50 to 85, 50 to 80, 50 to 75, 50 to 70, 50 to 65, 50 to 60, 50 to 55, 55 to 100, 55 to 95, 55 to90, 55 to 85, 55 to 80, 55 to 75, 55 to 70, 55 to 65, 55 to 60, 60 to 100, 60 to 95, 60 to 90, 60 to85, 60 to 80, 60 to 75, 60 to 70, 60 to 65, 65 to 100, 65 to 95, 65 to 90, 65 to 85, 65 to 80, 65 to 75, 65 to 70, 70 to 100, 70 to 95, 70 to 90, 70 to 85, 70 to 80, 70 to 75, 75 to 100, 75 to 95, 75 to 90, 75 to 85, 75 to 80, 80 to 100, 80 to 95, 80 to 90, 80 to 85, 85 to 100, 85 to 95, 85 to 90, 90 to 100, 90 to 95, or 95 to 100 consecutive amino acids. In certain embodiments, the synthetic peptide consists essentially of (or consists of) 6 to 15 consecutive amino acids.

[0175] In certain embodiments, a synthetic peptide of the disclosure consists essentially of (or consists of) an amino acid sequence of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 consecutive amino acids. In certain embodiments, the synthetic peptide consists essentially of (or consists of) 6, 7, or 15 consecutive amino acids.

[0176] In certain embodiments, a synthetic peptide of the disclosure is 5 to 100 (e.g., 5 to 60, e.g., 5 to 30) amino acids in length. For example, in certain embodiments, the synthetic peptide is 5 to 100, 5 to 95, 5 to 90, 5 to 85, 5 to 80, 5 to 75, 5 to 70, 5 to 65, 5 to 60, 5 to 55, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 19, 5 to 18, 5 to 17, 5 to 16, 5 to 15, 5 to 14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 6 to 100, 6 to 95, 6 to 90, 6 to 85, 6 to 80, 6o 75, 6 to 70, 6 to 65, 6 to 60, 6 to 55, 6 to 50, 6 to 45, 6 to 40, 6 to 35, 6 to 30, 6 to 25, 6 to 20,6 to 19, 6 to 18, 6 to 17, 6 to 16, 6 to 15, 6 to 14, 6 to 13, 6 to 12, 6 to 11, 6 to 10, 6 to 9, 6 to 8, 6o 7, 7 to 100, 7 to 95, 7 to 90, 7 to 85, 7 to 80, 7 to 75, 7 to 70, 7 to 65, 7 to 60, 7 to 55, 7 to 50,7 to 45, 7 to 40, 7 to 35, 7 to 30, 7 to 25, 7 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 7 to14, 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 7 to 8, 8 to 100, 8 to 95, 8 to 90, 8 to 85, 8 to 80, 8 to75, 8 to 70, 8 to 65, 8 to 60, 8 to 55, 8 to 50, 8 to 45, 8 to 40, 8 to 35, 8 to 30, 8 to 25, 8 to 20, 8o 19, 8 to 18, 8 to 17, 8 to 16, 8 to 15, 8 to 14, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 100, 9 to 95, 9 to 90, 9 to 85, 9 to 80, 9 to 75, 9 to 70, 9 to 65, 9 to 60, 9 to 55, 9 to 50, 9 to 45, 9 to 0, 9 to 35, 9 to 30, 9 to 25, 9 to 20, 9 to 19, 9 to 18, 9 to 17, 9 to 16, 9 to 15, 9 to 14, 9 to 13, 9o 12, 9 to 11, 9 to 10, 10 to 100, 10 to 95, 10 to 90, 10 to 85, 10 to 80, 10 to 75, 10 to 70, 10 to 65, 10 to 60, 10 to 55, 10 to 50, 10 to 45, 10 to 40, 10 to 35, 10 to 30, 10 to 25, 10 to 20, 10 to19, 10 to 18, 10 to 17, 10 to 16, 10 to 15, 10 to 14, 10 to 13, 10 to 12, 10 to 11, 11 to 100, 11 to95, 11 to 90, 11 to 85, 11 to 80, 11 to 75, 11 to 70, 11 to 65, 11 to 60, 11 to 55, 11 to 50, 11 to 5, 11 to 40, 11 to 35, 11 to 30, 11 to 25, 11 to 20, 11 to 19, 11 to 18, 11 to 17, 11 to 16, 11 to15, 11 to 14, 11 to 13, 11 to 12, 12 to 100, 12 to 95, 12 to 90, 12 to 85, 12 to 80, 12 to 75, 12 to70, 12 to 65, 12 to 60, 12 to 55, 12 to 50, 12 to 45, 12 to 40, 12 to 35, 12 to 30, 12 to 25, 12 to 0, 12 to 19, 12 to 18, 12 to 17, 12 to 16, 12 to 15, 12 to 14, 12 to 13, 13 to 100, 13 to 95, 13 to90, 13 to 85, 13 to 80, 13 to 75, 13 to 70, 13 to 65, 13 to 60, 13 to 55, 13 to 50, 13 to 45, 13 to 0, 13 to 35, 13 to 30, 13 to 25, 13 to 20, 13 to 19, 13 to 18, 13 to 17, 13 to 16, 13 to 15, 13 to14, 14 to 100, 14 to 95, 14 to 90, 14 to 85, 14 to 80, 14 to 75, 14 to 70, 14 to 65, 14 to 60, 14 to 55, 14 to 50, 14 to 45, 14 to 40, 14 to 35, 14 to 30, 14 to 25, 14 to 20, 14 to 19, 14 to 18, 14 to 17, 14 to 16, 14 to 15, 15 to 100, 15 to 95, 15 to 90, 15 to 85, 15 to 80, 15 to 75, 15 to 70, 15 to 65, 15 to 60, 15 to 55, 15 to 50, 15 to 45, 15 to 40, 15 to 3515 to 30, 15 to 25, 15 to 20, 15 to 19,15 to 18, 15 to 17, 15 to 16, 16 to 100, 16 to 95, 16 to 90, 16 to 85, 16 to 80, 16 to 75, 16 to 70,16 to 65, 16 to 60, 16 to 55, 16 to 50, 16 to 45, 16 to 40, 16 to 35, 16 to 30, 16 to 25, 16 to 20, 16o 19, 16 to 18, 16 to 17, 17 to 100, 17 to 95, 17 to 90, 17 to 85, 17 to 80, 17 to 75, 17 to 70, 17o 65, 17 to 60, 17 to 55, 17 to 50, 17 to 45, 17 to 40, 17 to 35, 17 to 30, 17 to 25, 17 to 20, 17 to 19, 17 to 18, 18 to 100, 18 to 95, 18 to 90, 18 to 85, 18 to 80, 18 to 75, 18 to 70, 18 to 65, 18 to 60, 18 to 55, 18 to 50, 18 to 45, 18 to 40, 18 to 35, 18 to 30, 18 to 25, 18 to 20, 18 to 19, 19 to 100, 19 to 95, 19 to 90, 19 to 85, 19 to 80, 19 to 75, 19 to 70, 19 to 65, 19 to 60, 19 to 55, 19 to 50, 19 to 45, 19 to 40, 19 to 35, 19 to 30, 19 to 25, 19 to 20, 20 to 100, 20 to 95, 20 to 90, 20 to85, 20 to 80, 20 to 75, 20 to 70, 20 to 65, 20 to 60, 20 to 55, 20 to 50, 20 to 45, 20 to 40, 20 to35, 20 to 30, 20 to 25, 25 to 100, 25 to 95, 25 to 90, 25 to 85, 25 to 80, 25 to 75, 25 to 70, 25 to65, 25 to 60, 25 to 55, 25 to 50, 25 to 45, 25 to 40, 25 to 35, 25 to 30, 30 to 100, 30 to 95, 30 to90, 30 to 85, 30 to 80, 30 to 75, 30 to 70, 30 to 65, 30 to 60, 30 to 55, 30 to 50, 30 to 45, 30 to 40, 30 to 35, 35 to 100, 35 to 95, 35 to 90, 35 to 85, 35 to 80, 35 to 75, 35 to 70, 35 to 65, 35 to60, 35 to 55, 35 to 50, 35 to 45, 35 to 40, 40 to 100, 40 to 95, 40 to 90, 40 to 85, 40 to 80, 40 to75, 40 to 70, 40 to 65, 40 to 60, 40 to 55, 40 to 50, 40 to 45, 45 to 100, 45 to 95, 45 to 90, 45 to85, 45 to 80, 45 to 75, 45 to 70, 45 to 65, 45 to 60, 45 to 55, 45 to 50, 50 to 100, 50 to 95, 50 to90, 50 to 85, 50 to 80, 50 to 75, 50 to 70, 50 to 65, 50 to 60, 50 to 55, 55 to 100, 55 to 95, 55 to90, 55 to 85, 55 to 80, 55 to 75, 55 to 70, 55 to 65, 55 to 60, 60 to 100, 60 to 95, 60 to 90, 60 to85, 60 to 80, 60 to 75, 60 to 70, 60 to 65, 65 to 100, 65 to 95, 65 to 90, 65 to 85, 65 to 80, 65 to75, 65 to 70, 70 to 100, 70 to 95, 70 to 90, 70 to 85, 70 to 80, 70 to 75, 75 to 100, 75 to 95, 75 to90, 75 to 85, 75 to 80, 80 to 100, 80 to 95, 80 to 90, 80 to 85, 85 to 100, 85 to 95, 85 to 90, 90 to100, 90 to 95, or 95 to 100 amino acids in length. In certain embodiments, the synthetic peptide is 6 to 15 amino acids in length.

[0177] In certain embodiments, the synthetic peptide is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 consecutive amino acids in length. In certain embodiments, the synthetic peptide is 6, 7, or 15 amino acids in length.

[0178] In certain embodiments, a synthetic peptide of the disclosure comprises at least one or at least two amino acid residues that are covalently linked to a chemical moiety, e.g., a moiety not naturally found in a naturally occurring peptide. In certain embodiments, the N-terminal and / or the C-terminal amino acid of the synthetic peptide is modified by the addition of a chemical moiety, e.g., a moiety not naturally found in a naturally occurring peptide. In certain embodiments, the N-terminal amino acid is modified by the addition of an acetyl group or a pyroglutamic acid. In certain embodiments, the N-terminal amino acid is acetylated. In certain embodiments, the C-terminal amino acid is modified by the addition of an amide group or an ethylamide group. In certain embodiments, the C-terminal amino acid is amidated.

[0179] In certain embodiments, the KD value with which a synthetic peptide of the disclosure binds NCK1 is less than or equal to 1 mM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 450 pM, 400 pM, 350 pM, 300 pM, 250 pM, 200 pM, 175 pM, 150 pM, 125 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, or 50 pM, for example, as determined by isothermal titration calorimetry (ITC). In certain embodiments, the KD value with which a synthetic peptide of the disclosure binds the SH3-2 domain of NCK1 is less than or equal to 1 mM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 450 pM, 400 pM, 350 pM, 300 pM, 250 pM, 200 pM, 175 pM, 150 pM, 125 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, or 50 pM, for example, as determined by ITC.

[0180] In certain embodiments, a synthetic peptide of the disclosure is a 7-mer peptide comprising or consisting essentially of the amino acid sequence of SEQ ID NO: 9, wherein the N-terminus is acetylated and the and the C-terminus is in amide form. In certain embodiments, the molecular formula of the peptide is C40H69N15O8, and / or the molecular weight of the peptide is 888.1 g / mol. In certain embodiments, the synthetic peptide is formulated as a bis-acetate salt, optionally wherein the molecular formula of the bis-acetate salt is C44H77N15O12 and / or the molecular weight of the bis-acetate salt is 1008.2 g / mol. In certain embodiments, the synthetic peptide is formulated as a tri-acetate salt, optionally wherein the molecular formula of the triacetate salt is C46H81N15O14 and / or the molecular weight of the tri-acetate salt is 1068.2 g / mol. a. Six- to 30-mer or Six to 50-mer Synthetic Peptides with PXPPXR Motif (SEQ ID NO: 1)

[0181] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of 6 to 30 (e.g., 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, 6 to 30), or 6 to 50 (e.g., 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, 6 to 30, 6 to 31, 6 to 32, 6 to 33, 6 to 34, 6 to 35, 6 to 36, 6 to 37, 6 to 38, 6 to 39, 6 to 40, 6 to 41, 6 to 42, 6 to 43, 6 to 44, 6 to 45, 6 to 46, 6 to 47, 6 to 48, 6 to 49 or 6 to 50) consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO 1 :PX1PPX2R (SEQ ID NO: 1), wherein Xi and X2 are each independently any amino acid, wherein: (i) the proline in position 1 of SEQ ID NO: 1 is the N-terminal amino acid; (ii) the N-terminal amino acid is chemically modified (e.g., acetylated) and / or the C-terminal amino acid is chemically modified (e.g., amidated); and / or (iii) the C-terminal amino acid is arginine provided that, (1) if X2 is arginine, then Xi is not arginine or glutamine, (2) if X2 is serine, Xi is not arginine, and (3) if X2 is methionine, then Xi is not histidine. In certain embodiments wherein the proline in position 1 is the N-terminal amino acid, the proline in position 1 is modified with a chemical moiety (e.g, by covalent linkage to a carbonyl-containing moiety, e.g, an acetyl moiety).

[0182] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0183] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0184] In certain embodiments, X2 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X2 is arginine, histidine, or lysine. In certain embodiments, X2 is lysine. In certain embodiments, X2 is glutamic acid. In certain embodiments, X2 is an uncharged amino acid. In certain embodiments, X2 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X2 is a hydrophobic amino acid. In certain embodiments, X2 is alanine, cysteine, or tryptophan.

[0185] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0186] In certain embodiments, Xi and X2 are both charged amino acids. In certain embodiments, Xi and X2 are both positively charged amino acids. In certain embodiments, Xi and X2 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X2 is lysine.

[0187] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 1. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected fromthe group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. b. Seven- to Ten-mer Synthetic Peptides with PXXPXR Motif (SEQ ID NO: 2)

[0188] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 7 to 10 consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) wherein: (i) Xi and X3 are each independently any amino acid, and X2 is a non-aromatic amino acid; (ii) if Xi is alanine and X2 is valine, then X3 is not proline; (iii) if X2 is proline and X3 is arginine, then Xi is not arginine or glutamine; and (iv) if X2 is proline and X3 is methionine, then Xi is not histidine. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, the amino acid is modified with a chemical moiety (e.g., covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety.

[0189] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0190] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0191] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 isalanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0192] In certain embodiments X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0193] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0194] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0195] In certain embodiments, Xi and X3 are both charged amino acids. In certain embodiments, Xi and X3 are both positively charged amino acids. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X3 is lysine.

[0196] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g., a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline.

[0197] In certain embodiments, X2 is an uncharged amino acid, e.g., a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine.

[0198] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; and / or X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; and / or X3 is arginine, histidine, or lysine. In certain embodiments, Xi is arginine, X2 is proline, and X3 is lysine.

[0199] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 2. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0200] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 7 to 10 consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) wherein: (i) Xi and X3 are each independently any amino acid, and X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; (ii) if Xi is alanine and X2 is valine, then X3 is not proline; (iii) if X2 is proline and X3 is arginine, then Xi is not arginine or glutamine; and (iv) if X2 is proline and X3 is methionine, then Xi is not histidine. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, the amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0201] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine,aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0202] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0203] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0204] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 2. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. c. 11-mer Synthetic Peptides with PXXPXRX Motif (SEQ ID NO: 3)

[0205] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of eleven consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (a) Xi and X3 are each independently any amino acid, X2 is a non-aromatic amino acid, and X4 is either absent or any amino acid, and (b) wherein if X2 is proline and X4is not absent, then: (i) Xi is not threonine; (ii) X3 is not lysine; and / or (iii) X4 is not serine. In certainembodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0206] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0207] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0208] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 is alanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0209] In certain embodiments X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0210] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0211] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0212] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0213] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0214] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0215] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g., a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0216] In certain embodiments, X2 is an uncharged amino acid, e.g., a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0217] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid; and / or X4 is absent. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; X3 is arginine, histidine, or lysine; and X4 is absent. In certain embodiments, Xi is arginine, X2 is proline, X3 is lysine, and X4 is absent.

[0218] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0219] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of eleven consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3),wherein: (a) Xi and X3 are each independently any amino acid; (b) X2 is selected from the group consisting of alanine, arginine isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and (c) X4 is either absent or any amino acid, and (d) wherein if X2 is proline and Xus not absent, then: (i) Xi is not threonine; (ii) X3 is not lysine; and / or (iii) X4 is not serine. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N- terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0220] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0221] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0222] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0223] In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting ofaspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0224] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. d. 12-mer Synthetic Peptides with PXXPXRX Motif (SEQ ID NO: 3)

[0225] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 12 consecutive amino acids, including an N- terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (a) Xi and X3 are each independently any amino acid, X2 is a non-aromatic amino acid, and X4 is either absent or any amino acid, and (b) wherein if X2 is proline and X4 is not absent, then (i) Xi is not arginine; (ii) X3 is not threonine; and / or (iii) X4 is not threonine. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid ofthe synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0226] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0227] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0228] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 is alanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0229] In certain embodiments X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0230] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0231] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0232] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0233] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0234] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certainembodiments, Xi is arginine and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0235] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g., a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0236] In certain embodiments, X2 is an uncharged amino acid, e.g., a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0237] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid; and / or X4 is absent. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; X3 is arginine, histidine, or lysine; and X4 is absent. In certain embodiments, Xi is arginine, X2 is proline, X3 is lysine, and X4 is absent.

[0238] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0239] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 12 consecutive amino acids, including an N- terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (a) Xi and X3 are each independently any amino acid; (b) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine,tyrosine, and valine; (c) X4 is either absent or any amino acid, and (d) wherein if X2 is proline and X4 is not absent, then (i) Xi is not arginine; (ii) X3 is not threonine; and / or (iii) X4 is not threonine. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N- terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0240] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0241] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0242] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0243] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0244] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is apositively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0245] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. e. 13-mer Synthetic Peptides with PXXPXRX Motif (SEQ ID NO: 3)

[0246] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 13 consecutive amino acids, including an N- terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3),wherein Xi and X3 are each independently any amino acid, X2 is a non-aromatic amino acid, and X4 is either absent or any amino acid. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0247] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0248] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0249] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 is alanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0250] In certain embodiments X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0251] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments,Xs is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0252] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0253] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0254] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine,and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0255] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0256] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g, a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0257] In certain embodiments, X2 is an uncharged amino acid, e.g, a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0258] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid; and / or X4 is absent. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; X3 is arginine, histidine, or lysine; and X4 is absent. In certain embodiments, Xi is arginine, X2 is proline, X3 is lysine, and X4 is absent.

[0259] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0260] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 13 consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein Xi and X3 are each independently any amino acid, X2 is selected from the group consisting of alanine, arginine isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine, and X4 is either absent or any amino acid. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0261] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0262] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0263] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0264] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0265] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0266] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. f. 14-mer Synthetic Peptides with PXXPXRX Motif (SEQ ID NO: 3)

[0267] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 14 consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid, X2 is a non-aromatic amino acid, and X4 is either absent or any amino acid; (2) if Xi is alanine and X2 is valine, then X3 is not proline; and (3) if X2 is proline and X4 is absent, then: (i) Xi is not arginine; and / or (ii) X3 is not serine. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N- terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0268] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0269] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0270] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 is alanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0271] In certain embodiments X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0272] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0273] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0274] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0275] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serineand threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0276] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0277] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g., a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0278] In certain embodiments, X2 is an uncharged amino acid, e.g., a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0279] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid; and / or X4 is absent. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; X3 is arginine, histidine, or lysine; and X4 is absent. In certain embodiments, Xi is arginine, X2 is proline, X3 is lysine, and X4 is absent.

[0280] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0281] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 14 consecutive amino acids, including an N- terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; (3) if Xi is alanine and X2 is valine, then X3 is not proline; and (4) if X2 is proline and X4 is absent, then: (i) Xi is not arginine; and / or (ii) X3 is not serine. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0282] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0283] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0284] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine,cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0285] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0286] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0287] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.g. 15-mer Synthetic Peptides with PXXPXRX Motif (SEQ ID NO: 3)

[0288] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 15 consecutive amino acids, including an N- terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid, X2 is a non-aromatic amino acid, and X4 is either absent or any amino acid; and (2) wherein if X2 is proline and X4 is not absent, then:(i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4 is not the C-terminal amino acid and / or the N-terminal amino acid is not a proline;(ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and(iii) if X4 is proline, then:(a) if Xi is methionine, then X3 is not asparagine; and(b) if Xi is arginine, then X3 is not glycine.In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0289] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0290] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine,aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0291] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 is alanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0292] In certain embodiments X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0293] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0294] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0295] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0296] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid,e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0297] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0298] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g., a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0299] In certain embodiments, X2 is an uncharged amino acid, e.g., a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0300] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; X3 is a charged amino acid,e.g., a positively charged amino acid; and / or X4 is absent. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; X3 is arginine, histidine, or lysine; and X4 is absent. In certain embodiments, Xi is arginine, X2 is proline, X3 is lysine, and X4 is absent.

[0301] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0302] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of 15 consecutive amino acids, including an N- terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid, (2) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine, and (3) X4 is either absent or any amino acid; and (4) wherein if X2 is proline and X4 is not absent, then:(i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4 is not the C-terminal amino acid and / or the N-terminal amino acid is not a proline;(ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and(iii) if X4 is proline, then:(a) if Xi is methionine, then X3 is not asparagine; and(b) if Xi is arginine, then X3 is not glycine.

[0303] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0304] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0305] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0306] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0307] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the groupconsisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0308] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. h. 16- to 30-mer or 16- to 50-mer Synthetic Peptides with PXXPXRX Motif (SEQ ID NO: 3)

[0309] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of (i) sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twentyseven, twenty-eight, twenty-nine, or thirty consecutive amino acids, or (ii) sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty -three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty- two, forty-three, forty-four, forty-five, forty-six, forty-seven, forty-eight, forty-nine, or fifty consecutive amino acids, each including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid, X2 is a non-aromatic amino acid, and X4 is either absent or any amino acid; and (2) wherein, if the synthetic peptide consists essentially of twenty consecutive amino acids, then the four most C-terminal amino acid residues of the synthetic peptide is not SLSR (SEQ ID NO: 85). In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, theN-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0310] In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety.

[0311] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0312] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0313] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 is alanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0314] In certain embodiments X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0315] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments,Xs is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0316] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0317] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0318] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine,and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0319] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0320] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g, a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0321] In certain embodiments, X2 is an uncharged amino acid, e.g, a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine. In certain embodiments of the foregoing peptides, X4 is absent or X4 is isoleucine.

[0322] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; X3 is a charged amino acid, e.g., a positively charged amino acid; and / or X4 is absent. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; X3 is arginine, histidine, or lysine; and X4 is absent. In certain embodiments, Xi is arginine, X2 is proline, X3 is lysine, and X4 is absent.

[0323] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0324] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of (i) sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, or thirty consecutive amino acids, or (ii) sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty -three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty- two, forty-three, forty-four, forty-five, forty-six, forty-seven, forty-eight, forty-nine, or fifty consecutive amino acids, each including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3), wherein: (1) Xi and X3 are each independently any amino acid; (2) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; (3) X4 is either absent or any amino acid; and (4) wherein, if the synthetic peptide consists essentially of twenty consecutive amino acids, then the four most C-terminal amino acid residues of the synthetic peptide is not SLSR (SEQ ID NO: 85). In certain embodiments wherein the proline at position 1 of SEQ ID NO: 3 is the N-terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0325] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0326] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0327] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine,asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0328] In certain embodiments, X4 is absent and the arginine in position 6 of SEQ ID NO: 3 is the C-terminal amino acid.

[0329] In certain embodiments, X4 is present and is selected from any amino acid. In certain embodiments, X4 is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, X4 is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X4 is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments, X4 is isoleucine. In certain embodiments, X4 is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, X4 is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, X4 is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, X4 is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, X4 is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, X4 is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0330] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 3. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected fromthe group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. i. Six- to 30-mer or Six- to 50-mer Synthetic Peptides with PRPPKRX Motif (SEQ ID NO: 4)

[0331] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of an amino acid sequence of (i) 6 to 30, e.g., 6 to 29, 6 to 28, 6 to 27, 6 to 26, 6 to 25, 6 to 24, 6 to 23, 6 to 22, 6 to 21, 6 to 20, 6 to 19, 6 to 18, 6 to 17, 6 to 16, or 6 to 15 consecutive amino acids or (ii) 6 to 50, e.g., 6 to 49, 6 to 48, 6 to 47, 6 to 46, 6 to 45, 6 to 44, 6 to 43, 6 to 42, 6 to 41, 6 to 40, 6 to 39, 6 to 38, 6 to 37, 6 to 36, 6 to 35, 6 to 34, 6 to 33, 6 to 32, 6 to 31, 6 to 30, 6 to 29, 6 to 28, 6 to 27, 6 to 26, 6 to 25, 6 to 24, 6 to 23, 6 to 22, 6 to 21, 6 to 20, 6 to 19, 6 to 18, 6 to 17, 6 to 16, or 6 to 15 consecutive amino acids, each including an N- terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 4:PRPPKRX i (SEQ ID NO: 4), wherein: (1) Xi is absent or any amino acid, and (2) if Xi is isoleucine and the synthetic peptide is a 15-mer, then Xi is not the C-terminal amino acid and / or proline is not the N-terminal amino acid. In certain embodiments wherein the proline at position 1 of SEQ ID NO: 4 is the N- terminal amino acid of the synthetic peptide, the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety, e.g., an acetyl moiety).

[0332] In certain embodiments, Xi is absent and the arginine in position 6 of SEQ ID NO: 4 is the C-terminal amino acid. In certain embodiments, Xi is present and is selected from any amino acid. In certain embodiments, Xi is a charged amino acid, an uncharged amino acid, a hydrophobic amino acid, a hydrophilic amino acid, and / or a non-aromatic amino acid. In certain embodiments, Xi is a positively charged amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, Xi is a negatively charged amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, Xi is an uncharged amino acid, e.g., an amino acid selected from the group consisting of alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xi is an aliphatic amino acid, e.g., an amino acid selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine. In certain embodiments,Xi is isoleucine. In certain embodiments, Xi is an aromatic amino acid, e.g., an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine. In certain embodiments, Xi is a sulfur-containing amino acid, e.g., an amino acid selected from the group consisting of cysteine and methionine. In certain embodiments, Xi is an amino acid with a hydroxyl-containing side chain, e.g., an amino acid selected from the group consisting of serine and threonine. In certain embodiments, Xi is an acidic amino acid, e.g., an amino acid selected from the group consisting of aspartic acid and glutamic acid. In certain embodiments, Xi is a basic amino acid, e.g., an amino acid selected from the group consisting of arginine, histidine, and lysine. In certain embodiments, Xi is an amino acid with an amide-containing side chain, e.g., an amino acid selected from the group consisting of asparagine and glutamine.

[0333] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 4. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0334] In certain embodiments, the synthetic peptide comprises or consists essentially of the amino acid sequence of any one of SEQ ID NOs: 5-10. j. Six- to 30-mer or Six- to 50-mer Synthetic Peptides with PXXPXR Motif (SEQ ID NO: 2)

[0335] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of (i) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, or 6 to 30 consecutive amino acids, or (ii) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, 6 to 30, 6 to 31, 6 to 32, 6 to 33, 6 to 34, 6 to 35, 6 to 36, 6 to 37, 6 to 38, 6 to 39, 6 to 40, 6 to 41, 6 to 42, 6 to 43, 6 to 44, 6 to 45, 6 to 46, 6 to 47, 6 to 48, 6 to 49, or 6 to 50 consecutive amino acids, each including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO 2:PX1X2PX3R (SEQ ID NO: 2), wherein (i) Xi and X3 are each independently any amino acid; (ii) X2 is selected from the group consisting of selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine,phenylalanine, proline, threonine, tyrosine, and valine; and (iii) the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a KD of < 1,000 pM (e.g., <1,000 pM, <600 pM, or <300 pM), for example, as determined by isothermal titration calorimetry (ITC).

[0336] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0337] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0338] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0339] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 2. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0340] In certain embodiments, the synthetic peptide consists essentially of an amino acid sequence of at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen consecutive amino acids.

[0341] In certain embodiments, the synthetic peptide comprises or consists essentially of the amino acid sequence of any one of SEQ ID NOs: 5-10.

[0342] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of (i) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, or 6 to 30 consecutive amino acids, or (ii) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, 6 to 30, 6 to 31, 6 to 32, 6 to 33, 6 to 34, 6 to 35, 6 to 36, 6 to 37, 6 to 38, 6 to 39, 6 to 40, 6 to 41, 6 to 42, 6 to 43, 6 to 44, 6 to 45, 6 to 46, 6 to 47, 6 to 48, 6 to 49, or 6 to 50 consecutive amino acids, each including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO 2:PX1X2PX3R (SEQ ID NO: 2), wherein (i) Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine; (ii) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and (iii) X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0343] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0344] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0345] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0346] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 2. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0347] In certain embodiments, the synthetic peptide consists essentially of an amino acid sequence of at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen consecutive amino acids.

[0348] In certain embodiments, the synthetic peptide comprises or consists essentially of the amino acid sequence of any one of SEQ ID NOs: 5-10.

[0349] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of (i) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, or 6 to 30 consecutive amino acids, or (ii) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, 6 to 30, 6 to 31, 6 to 32, 6 to 33, 6 to 34, 6 to 35, 6 to 36, 6 to 37, 6 to 38, 6 to 39, 6 to 40, 6 to 41, 6 to 42, 6 to 43, 6 to 44, 6 to 45, 6 to 46, 6 to 47, 6 to 48, 6 to 49, or 6 to 50 consecutive amino acids, each including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO 2:PX1X2PX3R (SEQ ID NO: 2), wherein (i) Xi and X3 are each independently any amino acid, and (ii) X2 is a non-aromatic amino acid.

[0350] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine,histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0351] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0352] In certain embodiments, X2 is an uncharged, non-aromatic amino acid. In certain embodiments, X2 is alanine or proline. In certain embodiments, X2 is proline. In certain embodiments, X2 is a hydrophobic, non-aromatic amino acid. In certain embodiments, X2 is alanine. In certain embodiments, X2 is a charged amino acid, for example, a positively charged amino acid. In certain embodiments, X2 is arginine.

[0353] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0354] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0355] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 isglutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0356] In certain embodiments, Xi and X3 are both charged amino acids. In certain embodiments, Xi and X3 are both positively charged amino acids. In certain embodiments, Xi and X3 are each independently selected from arginine, histidine, and lysine. In certain embodiments, Xi is arginine and X3 is lysine.

[0357] In certain embodiments, Xi is a charged amino acid, e.g. a positively charged amino acid, and X2 is an uncharged amino acid, e.g., a hydrophobic amino acid. In certain embodiments, Xi is arginine, histidine or lysine, and X2 is alanine or proline. In certain embodiments, Xi is arginine and X2 is proline.

[0358] In certain embodiments, X2 is an uncharged amino acid, e.g., a hydrophobic amino acid, and X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, X2 is alanine or proline, and X3 is arginine, histidine or lysine. In certain embodiments, X2 is proline and X3 is lysine.

[0359] In certain embodiments, Xi is a charged amino acid, e.g., a positively charged amino acid; X2 is an uncharged amino acid, e.g., a hydrophobic amino acid; and / or X3 is a charged amino acid, e.g., a positively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine; X2 is alanine or proline; and / or X3 is arginine, histidine, or lysine. In certain embodiments, Xi is arginine, X2 is proline, and X3 is lysine.

[0360] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 2. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0361] In certain embodiments, the synthetic peptide consists essentially of an amino acid sequence of at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen consecutive amino acids.

[0362] In certain embodiments, the synthetic peptide comprises or consists essentially of the amino acid sequence of any one of SEQ ID NOs: 5-10.

[0363] In certain embodiments described herein, the disclosure relates to a synthetic peptide consisting essentially of (i) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, or 6 to 30 consecutive amino acids, or (ii) 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 21, 6 to 22, 6 to 23, 6 to 24, 6 to 25, 6 to 26, 6 to 27, 6 to 28, 6 to 29, 6 to 30, 6 to 31, 6 to 32, 6 to 33, 6 to 34, 6 to 35, 6 to 36, 6 to 37, 6 to 38, 6 to 39, 6 to 40, 6 to 41, 6 to 42, 6 to 43, 6 to 44, 6 to 45, 6 to 46, 6 to 47, 6 to 48, 6 to 49, or 6 to 50 consecutive amino acids, each including an N-terminal amino acid and a C-terminal amino acid, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO 2:PX1X2PX3R (SEQ ID NO: 2), wherein (i) Xi and X3 are each independently any amino acid, and (ii) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine.

[0364] In certain embodiments, Xi is a charged amino acid, for example, a positively charged amino acid or a negatively charged amino acid. In certain embodiments, Xi is arginine, histidine, or lysine. In certain embodiments, Xi is arginine. In certain embodiments, Xi is glutamic acid. In certain embodiments, Xi is an uncharged amino acid. In certain embodiments, Xi is a hydrophobic amino acid. In certain embodiments, Xi is alanine, asparagine, or serine.

[0365] In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. In certain embodiments, Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

[0366] In certain embodiments, X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine. In certain embodiments, X2 is selected from the group consisting of alanine, isoleucine, proline, and valine. In certain embodiments, X2 is selected from the group consisting of isoleucine, proline, and valine.

[0367] In certain embodiments, X3 is a charged amino acid, for example a positively charged amino acid or a negatively charged amino acid. In certain embodiments, X3 is arginine, histidine, or lysine. In certain embodiments, X3 is lysine. In certain embodiments, X3 is glutamic acid. In certain embodiments, X3 is an uncharged amino acid. In certain embodiments, X3 is alanine, asparagine, cysteine, serine, or tryptophan. In certain embodiments, X3 is a hydrophobic amino acid. In certain embodiments, X3 is alanine, cysteine, or tryptophan.

[0368] In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0369] In certain embodiments, the synthetic peptide further comprises an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 2. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0370] In certain embodiments, the synthetic peptide consists essentially of an amino acid sequence of at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen consecutive amino acids.

[0371] In certain embodiments, the synthetic peptide comprises or consists essentially of the amino acid sequence of any one of SEQ ID NOs: 5-10.III. Pharmaceutical Compositions

[0372] For therapeutic use, a synthetic NCKl-binding peptide of the disclosure preferably is combined with a pharmaceutically acceptable carrier.

[0373] Pharmaceutically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Suitable formulations for use in the present disclosure are found in Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23d ed. 2020). For a brief review of methods for drug delivery, see, e.g., Langer, Science (1990) 249: 1527-1533, 1990.

[0374] In certain embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, betacyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; saltforming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants (see Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23d ed. 2020)).

[0375] The disclosure provides a pharmaceutical composition comprising a synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty, consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ IDNO: 2), wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine; X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; and X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0376] In certain embodiments, Xi is selected from (i) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine or (ii) alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine. Alternatively or in addition to each of the foregoing, X2 is selected from (i) the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine, (ii) the group consisting of alanine, isoleucine, proline, and valine or (iii) the group consisting of isoleucine, proline, and valine. Alternatively or in addition to each of the foregoing, X3 is selected from (i) the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine or (ii) the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0377] In certain embodiments, a synthetic NCKl-binding peptide of the disclosure is formulated as a salt, e.g., as an acetate salt. In certain embodiments, the acetate salt a bis-acetate salt or as a tri-acetate salt. In certain embodiments, the peptide is formulated as an acetate salt and combined with a pharmaceutically acceptable carrier. In certain embodiments, at least one amino acid or at least two amino acid residues are covalently linked to a chemical moiety not present in a natural amino acid. In certain embodiments, the disclosure provides a composition (e.g., a pharmaceutical composition) comprising a synthetic NCKl-binding peptide formulated as a free base or as a salt, as described herein.

[0378] In certain embodiments, a composition (e.g., a pharmaceutical composition) may comprise a synthetic NCKl-binding peptide of the disclosure, wherein the purity of the syntheticpeptide is at least 95%. For example, the purify of the synthetic peptide in the composition may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.

[0379] Pharmaceutical compositions containing a synthetic NCK1 -binding peptide as disclosed herein can optionally be dried, using any appropriate method known to those skilled in the art. The pharmaceutical composition can, for example, be freeze dried or lyophilized.

[0380] In certain embodiments, a pharmaceutical composition may contain nanoparticles, or lipid droplets, e.g., polymeric nanoparticles, liposomes, or micelles (See Anselmo et al. (2016) BIOENG. TRANSL. MED. 1 : 10-29).

[0381] In certain embodiments, a pharmaceutical composition may contain a sustained- or controlled-delivery formulation. Techniques for formulating sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Sustained-release preparations may include, e.g., porous polymeric microparticles or semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly (2- hydroxyethyl-inethacrylate), ethylene vinyl acetate, or poly-D(-)-3 -hydroxybutyric acid. Sustained release compositions may also include liposomes that can be prepared by any of several methods known in the art.

[0382] Pharmaceutical compositions containing a synthetic NCK1 -binding peptide as disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are subcutaneous (SC), intravenous (IV), intraperitoneal, intradermal, inhalation, transdermal, topical, transmucosal, intrathecal, and rectal administration. In certain embodiments, the synthetic peptide is administered by subcutaneous administration. .

[0383] Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23 d ed. 2020). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.

[0384] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0385] Pharmaceutical formulations preferably are sterile. Sterilization can be accomplished by any suitable method, e.g., filtration through sterile filtration membranes, gamma radiation, etc. Where the composition is lyophilized, filter sterilization can be conducted prior to or following lyophilization and reconstitution.

[0386] The compositions described herein may be administered locally or systemically. It is contemplated that the compositions described herein are generally administered by parenteral administration. Preparations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions. In certain embodiments, the pharmaceutical composition is administered subcutaneously or may be administered intravenously, e.g., via intravenous infusion. In certain embodiments, it is contemplated that the synthetic constructs disclosed herein can be administered by systemic administration.

[0387] In embodiments wherein the compositions (e.g., pharmaceutical compositions) of the disclosure are aqueous, the composition can comprise a synthetic peptide of the disclosure at a concentration of, e.g., 150 mg / mL to 400 mg / mL. For example, the concentration of the synthetic peptide in the aqueous composition can be 150 mg / mL to 400 mg / mL, 150 mg / mL to 300 mg / mL, 150 mg / mL to 200 mg / mL, 200 mg / mL to 400 mg / mL, 200 mg / mL to 300 mg / mL, or 300 mg / mL to 400 mg / mL. In certain embodiments, the concentration of the synthetic peptide in the aqueous composition is 150 mg / mL, 200 mg / mL, 300 mg / mL, or 400 mg / mL. In certain embodiments, the aqueous composition is injectable (e.g, suitable for subcutaneous injection).

[0388] Generally, a therapeutically effective amount of active component, for example, a synthetic NCKl-binding peptide of the disclosure, is in the range of 0.1 mg / kg to 100 mg / kg, e.g, 1 mg / kg to 100 mg / kg. In certain embodiments, the effective amount is in the range of 15 to 30 mg / kg. In certain embodiments, the effective amount is 15 mg / kg. In certain embodiments, the effective amount is 30 mg / kg. In certain embodiments, the effective amount is in the range of 30 mg / kg to 150 mg / kg, e.g., 30 mg / kg to 75 mg / kg or 75 mg / kg to 150 mg / kg. In certain embodiments, the effective amount is 30 mg / kg. In certain embodiments, the effectiveamount is 75 mg / kg. In certain embodiments, the effective amount is 150 mg / kg. In certain embodiments, the effective amount is in the range of 50 mg / kg to 350 mg / kg, e.g., 50 mg / kg to 175 mg / kg or 175 mg / kg to 350 mg / kg. In certain embodiments, the effective amount is 50 mg / kg. In certain embodiments, the effective amount is 175 mg / kg. In certain embodiments, the effective amount is 350 mg / kg. In certain embodiments, the effective amount of a synthetic NCK1 -binding peptide of the disclosure (e.g., formulated as an acetate salt) is in the range of 40 mg to 320 mg. For example, in certain embodiments, the effective amount is in the range of 40 mg to 320 mg, 40 mg to 240 mg, 40 mg to 160 mg, 40 mg to 80 mg, 80 mg to 320 mg, 80 mg to 240 mg, 80 mg to 160 mg, 160 mg to 320 mg, 160 mg to 240 mg, or 240 mg to 320 mg. In certain embodiments, the effective amount is 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg. In certain embodiments, the effective amount of a synthetic NCK1 -binding peptide of the disclosure (e.g., formulated or measured as a free base) is in the range of 30 mg to 270 mg. For example, in certain embodiments, the effective amount is in the range of 30 mg to 270 mg, 30 mg to 200 mg, 30 mg to 140 mg, 30 mg to 70 mg, 60 mg to 270 mg, 60 mg to 200 mg, 60 mg to 140 mg, 130 mg to 270 mg, 130 mg to 200 mg, or 190 mg to 270 mg. In certain embodiments, the effective amount is 30 mg, 60 mg, 70 mg, 130 mg, 140 mg, 190 mg, 200 mg, or 270 mg.

[0389] The amount administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health of the patient, the in vivo potency of the active component, the pharmaceutical formulation, and the route of administration. The initial dosage can be increased beyond the upper level in order to rapidly achieve the desired bloodlevel or tissue-level. Alternatively, the initial dosage can be smaller than the optimum, and the daily dosage may be progressively increased during the course of treatment. Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study. Dosing frequency can vary, depending on factors such as route of administration, dosage amount, serum half-life of the synthetic peptide, and the disease, disorder, or condition being treated. Exemplary dosing frequencies are once per day, once per week and once every two weeks.

[0390] The disclosure also provides a delivery system comprising (1) a composition (e.g., a pharmaceutical composition) disclosed herein, and (2) a delivery device. The composition can be, for example, a composition (e.g., a pharmaceutical composition) comprising a synthetic NCK1 -binding peptide of the disclosure, optionally wherein the peptide is formulated as a salt, e.g., an acetate salt, e.g., a bis-acetate salt or a tri-acetate salt. In certain embodiments, the delivery device is suitable for administering the composition comprising a synthetic peptide of the disclosure to a subject in need thereof, e.g., via subcutaneous or intravenous injection. In certain embodiments, the delivery device is a syringe, a pen delivery device, an injector deliverysystem, and / or an autoinjector. In certain embodiments, the delivery device is a syringe, e.g., a pre-filled syringe.IV. Methods and Therapeutic Uses

[0391] The disclosure also provides a method of modulating an activity of NCK1, wherein the method comprises contacting NCK1 with an agent that disrupts an interaction between PTP1B and NCK1, thereby modulating or inhibiting binding between NCK1 and PTP1B. In certain embodiments, the agent is a small molecule, protein, e.g., an antibody (e.g., an antibody or antigen binding fragment thereof that binds PTP1B or NCK1 to reduce or prevent the interaction between PTP1B and NCK1) or peptide, e.g., a synthetic peptide or composition of the disclosure that can reduce or prevent the interaction between PTP1B and NCK1. In certain embodiments, contacting NCK1 with the agent disrupts binding between PTP1B and NCK1. Binding of PTP1B and NCK1 can be measured using any number of techniques known in the art including, for example, via co-immunoprecipitation assays, via isothermal Titration Calorimetry (ITC), or via Surface Plasmon Resonance (SPR). In certain embodiments, contacting NCK1 results in modulating an activity of PTP1B. In certain embodiments, the activity of PTP1B is downregulation of the insulin receptor signaling pathway. In certain embodiments, the activity of PTP1B is dephosphorylation of the insulin receptor.

[0392] The disclosure also provides a method of increasing insulin receptor signaling, e.g., in a subject, cell, or tissue, wherein the method comprises contacting NCK1 with an agent, e.g., a protein, e.g., an antibody (e.g., an antibody or antigen binding fragment thereof that binds PTP1B or NCK1 to reduce or prevent the interaction between PTP1B and NCK1) or a peptide, e.g., a synthetic peptide or composition of the disclosure that can reduce or prevent the interaction between PTP1B and NCK1, thereby increasing insulin receptor signaling.

[0393] The present disclosure provides methods for decreasing or inhibiting binding between PTP1B and NCK1, by contacting NCK1 with an effective amount of an agent that disrupts an interaction between PTP1B and NCK1, thereby modulating or inhibiting binding between NCK1 and PTP1B. In certain embodiments, the agent is a small molecule, protein (e.g., an antibody or antigen fragment thereof that binds to PTP1B or NCK1), or a peptide (e.g., a synthetic NCK1- binding peptide as disclosed herein), each of which can disrupt or otherwise interfere with the formation of a PTP1B-NCK1 complex. In certain embodiments, the method is used to modulate an activity of PTP1B, e.g., PTP IB-mediated downregulation of insulin receptor signaling, thereby enhancing or restoring sensitivity to insulin and / or insulin receptor signaling in a cell or tissue. Without wishing to be bound by theory, it is believed that by using agents (e.g., peptides)that target and bind NCK1 (rather than PTP1B), that administration of the agent (e.g. peptide) will preferentially or specifically inhibit PTP1B activity that is dependent on interaction with the NCK1 adapter protein (e.g., downregulation of insulin receptor signaling), while having less or a minimal impact on, e.g., PTP IB-mediated regulation of other targets or pathways.

[0394] Each of the compositions and methods disclosed herein can be used to treat or prevent a disease or disorder associated with PTP1B and / or NCK1. In certain embodiments, the disclosure provides administering an agent (e.g., a peptide) that disrupts an interaction between PTP1B and NCK1 to a subject in need thereof. In certain embodiments, the agent is a NCK1- binding peptide of the disclosure. In certain embodiments, the agent is a NCKl-binding peptide as described in, e.g., any one of sections 11(a) through II(j) of this disclosure. In certain embodiments, the agent is a NCKl-binding peptide as described in section II(j) of this disclosure. In certain embodiments, the agent is a NCKl-binding peptide as set forth in Table 1 or Table 2. In certain embodiments, the agent is a NCKl-binding peptide as set forth in Table 2.

[0395] The disclosure provides a method of treating or preventing a disease or disorder associated with PTP1B and / or NCK1. In certain embodiments, the method comprises administering a NCKl-binding peptide of the disclosure to a subject in need thereof. The method can comprise administering to the subject an effective amount of a synthetic NCKl- binding peptide described herein, either alone or in a combination with another therapeutic agent to treat or prevent the disease or disorder in the subject. An effective amount of the peptide can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0396] In certain embodiments, the disease or disorder is a disease or disorder associated with NCK1 activity and / or PTP IB activity. In certain embodiments, the disease or disorder is a metabolic disease or disorder. In certain embodiments, the diseases or disorder is diabetes, obesity, insulin resistance, hyperlipidemia, or atherosclerosis. In certain embodiments, the disease or disorder is diabetes, e.g., Type 2 diabetes. In certain embodiments, the disease or disorder is obesity.

[0397] In one embodiment, the disclosure provides a method of treating or preventing diabetes (e.g., Type 2 diabetes) in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide described herein or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat or prevent diabetes in the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty consecutive amino acids including anN-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein (1) Xi and X3 are each independently any amino acid; and (2) X2 is a non-aromatic amino acid. In some embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0398] In another embodiment, the disclosure provides a method of treating or preventing diabetes (e.g., Type 2 diabetes) in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat or prevent diabetes in the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein (1) Xi and X3 are each independently any amino acid; and (2) X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine. In some embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0399] In addition, the disclosure provides a method of treating obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat obesity in the subject, wherein the synthetic peptide consists essentially of an amino acid sequence of (i) six to thirty or (ii) six to fifty, consecutive amino acids, including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of PX1X2PX3R (SEQ ID NO: 2), wherein: (1) Xi and X3 are each independently any amino acid; and (2) X2 is a non- aromatic amino acid. In some embodiments, if the proline at position 1 of SEQ ID NO: 2 is the N-terminal amino acid of the synthetic peptide, then the N-terminal amino acid is modified with a chemical moiety (e.g., by covalent linkage to a carbonyl-containing moiety).

[0400] In another embodiment, the disclosure provides a method of treating obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and apharmaceutically acceptable carrier, thereby to treat obesity ...

Claims

WHAT IS CLAIMED IS:

1. A synthetic peptide consisting essentially of an amino acid sequence of six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or six to fifty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 1PX1PPX2R (SEQ ID NO: 1) wherein Xi and X2 are each independently any amino acid, and(a) the proline at position 1 of SEQ ID NO: 1 is the N-terminal amino acid and is optionally modified by covalent linkage to a carbonyl-containing moiety;(b) the N-terminal amino acid is chemically modified (e.g., acetylated) and / or the C- terminal amino acid is chemically modified (e.g., amidated), or(c) the C-terminal amino acid is arginine provided that, (i) if X2 is arginine, then Xi is not arginine or glutamine, (ii) if X2 is serine, Xi is not arginine, and (iii) if X2 is methionine, then Xi is not a histidine.

2. The synthetic peptide of claim 1, consisting essentially of an amino acid sequence of six to thirty consecutive amino acids.

3. The synthetic peptide of claim 1, consisting essentially of an amino acid sequence of six to fifty consecutive amino acids.

4. A synthetic peptide consisting essentially of an amino acid sequence of six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or six to fifty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty,six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 1PX1PPX2R (SEQ ID NO: 1) wherein Xi and X2 are each independently any amino acid, and(a) the proline at position 1 of SEQ ID NO: 1 is the N-terminal amino acid and is optionally modified by covalent linkage to a carbonyl-containing moiety; or(b) the N-terminal amino acid is acetylated and the C-terminal amino acid is amidated.

5. The synthetic peptide of claim 4, consisting essentially of an amino acid sequence of six to thirty consecutive amino acids.

6. The synthetic peptide of claim 4, consisting essentially of an amino acid sequence of six to fifty consecutive amino acids.

7. The synthetic peptide of any one of claims 1-6, wherein Xi is a charged amino acid.

8. The synthetic peptide of claim 7, wherein Xi is a positively charged amino acid.

9. The synthetic peptide of claim 8, wherein Xi is selected from the group consisting of arginine, histidine, and lysine.

10. The synthetic peptide of claim 7, wherein Xi is a negatively charged amino acid.

11. The synthetic peptide of claim 10, wherein Xi is glutamic acid.

12. The synthetic peptide of claim any one of claims 1-6, wherein Xi is an uncharged amino acid.

13. The synthetic peptide of claim 12, wherein Xi is a hydrophobic amino acid.

14. The synthetic peptide of claim 12, wherein Xi is selected from the group consisting of alanine, asparagine, and serine.

15. The synthetic peptide of any one of claims 1-14, wherein X2 is a charged amino acid.

16. The synthetic peptide of claim 15, wherein X2 is a positively charged amino acid.

17. The synthetic peptide of claim 16, wherein X2 is arginine, histidine, or lysine.

18. The synthetic peptide of claim 17, wherein X2 is a negatively charged amino acid.

19. The synthetic peptide of claim 18, wherein X2 is glutamic acid.

20. The synthetic peptide of any one of claims 1-14, wherein X2 is an uncharged amino acid.

21. The synthetic peptide of claim 20, wherein X2 is selected from the group consisting of alanine, asparagine, cysteine, serine, and tryptophan.

22. The synthetic peptide of claim 20, wherein X2 is a hydrophobic amino acid.

23. The synthetic peptide of claim 22, wherein X2 is selected from the group consisting of alanine, cysteine, and tryptophan.

24. The synthetic peptide of claim any one of claims 1-6, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine.

25. The synthetic peptide of claim 24, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine.

26. The synthetic peptide of claim 25, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

27. The synthetic peptide of any one of claims 1-6, or 24-26, wherein X2 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

28. The synthetic peptide of claim 27, wherein X2 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

29. The synthetic peptide of claim 28, wherein X2is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

30. A synthetic peptide consisting essentially of an amino acid sequence of seven to ten consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid; if Xi is alanine and X2 is valine, then X3 is not proline; if X2 is proline and X3 is arginine, then Xi is not arginine or glutamine; and if X2 is proline and X3 is methionine, then Xi is not histidine.

31. A synthetic peptide consisting essentially of an amino acid sequence of eleven consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid;X4is either absent or any amino acid; and if X2 is proline and X4is not absent, then(i) Xi is not threonine;(ii) X3 is not lysine; and / or(iii) X4 is not serine.

32. A synthetic peptide consisting essentially of an amino acid sequence of twelve consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid;X4is either absent or any amino acid; if X2 is proline and Xns not absent, then(i) Xi is not arginine;(ii) X3 is not threonine; and / or(iii) X4 is not threonine.

33. A synthetic peptide consisting essentially of an amino acid sequence of thirteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid; andX4is either absent or any amino acid.

34. A synthetic peptide consisting essentially of an amino acid sequence of fourteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid;X4is either absent or any amino acid; if Xi is alanine and X2 is valine, then X3 is not proline; and if X2 is proline and X4is absent, then:(i) Xi is not arginine; and / or(ii) X3 is not serine.

35. A synthetic peptide consisting essentially of an amino acid sequence of fifteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid;X4is either absent or any amino acid; and if X2 is proline and X4is not absent, then:(i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4is not the C- terminal amino acid;(ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and(iii) if X4 is proline, then:(a) if Xi is methionine, then X3 is not asparagine; and(b) if Xi is arginine, then X3 is not glycine.

36. A synthetic peptide consisting essentially of an amino acid sequence of fifteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid;X4is either absent or any amino acid; and if X2 is proline and X4is not absent, then:(i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X4is not the C- terminal amino acid and / or the N-terminal amino acid is not a proline;(ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and(iii) if X4 is proline, then:(a) if Xi is methionine, then X3 is not asparagine; and(b) if Xi is arginine, then X3 is not glycine.

37. A synthetic peptide consisting essentially of an amino acid sequence of (i) sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty -two, twenty -three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, or thirty consecutive amino acids, or (ii) sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty- three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two, forty-three, forty-four, forty-five, forty-six, forty-seven, forty-eight, forty-nine, or fifty consecutive amino acids, each including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is a non-aromatic amino acid;X4is either absent or any amino acid; wherein, if the synthetic peptide consists essentially of twenty consecutive amino acids, then the four most C-terminal amino acid residues of the synthetic peptide is not SLSR (SEQ ID NO: 85).

38. The synthetic peptide of claim 37, consisting essentially of an amino acid sequence of sixteen to thirty consecutive amino acids.

39. The synthetic peptide of claim 37, consisting essentially of an amino acid sequence of sixteen to fifty consecutive amino acids.

40. The synthetic peptide of any one of claims 32-39, wherein Xi is a charged amino acid.

41. The synthetic peptide of claim 40, wherein Xi is a positively charged amino acid.

42. The synthetic peptide of claim 41, wherein Xi is arginine, histidine, or lysine.

43. The synthetic peptide of claim 40, wherein Xi is a negatively charged amino acid.

44. The synthetic peptide of claim 43, wherein Xi is glutamic acid.

45. The synthetic peptide of any one of claims 32-39, wherein Xi is an uncharged amino acid.

46. The synthetic peptide of claim 45, wherein Xi is a hydrophobic amino acid.

47. The synthetic peptide of claim 45, wherein Xi is selected from the group consisting of alanine, asparagine, and serine.

48. The synthetic peptide of any one of claims 32-47, wherein X2 is an uncharged, nonaromatic amino acid.

49. The synthetic peptide of claim 48, wherein X2 is alanine or proline.

50. The synthetic peptide of claim 48, wherein X2 is a hydrophobic, non-aromatic amino acid.

51. The synthetic peptide of claim 50, wherein X2 is alanine.

52. The synthetic peptide of any one of claims 32-47, wherein X2 is a charged amino acid.

53. The synthetic peptide of claim 52, wherein X2 is a positively charged amino acid.

54. The synthetic peptide of claim 53, wherein X2 is arginine.

55. The synthetic peptide of any one of claims 32-54, wherein X3 is a charged amino acid.

56. The synthetic peptide of claim 55, wherein X3 is a positively charged amino acid.

57. The synthetic peptide of claim 56, wherein X3 is arginine, histidine, or lysine.

58. The synthetic peptide of claim 55, wherein X3 is a negatively charged amino acid.

59. The synthetic peptide of claim 58, wherein X3 is glutamic acid.

60. The synthetic peptide of any one of claims 32-59, wherein X3 is an uncharged amino acid.

61. The synthetic peptide of claim 60, wherein X3 is selected from the group consisting of alanine, asparagine, cysteine, serine, and tryptophan.

62. The synthetic peptide of claim 60, wherein X3 is a hydrophobic amino acid.

63. The synthetic peptide of claim 62, wherein X3 is selected from the group consisting of alanine, cysteine, and tryptophan.

64. The synthetic peptide of claim 33-63, wherein Xus a charged amino acid.

65. The synthetic peptide of claim 64, wherein X s a positively charged amino acid.

66. The synthetic peptide of claim 65, wherein X s selected from the group consisting of arginine, histidine, and lysine.

67. The synthetic peptide of claim 64, wherein X-ds a negatively charged amino acid.

68. The synthetic peptide of claim 67, wherein X4 is aspartic acid or glutamic acid.

69. The synthetic peptide of claim 33-63, wherein Xus an uncharged amino acid.

70. The synthetic peptide of claim 69, wherein X s alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

71. The synthetic peptide of claim 33-63, wherein Xus an aliphatic amino acid.

72. The synthetic peptide of claim 71, wherein X s selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine.

73. The synthetic peptide of claim 72, wherein X s isoleucine.

74. The synthetic peptide of claim 33-63, wherein Xus an aromatic amino acid.

75. The synthetic peptide of claim 74, wherein X s phenylalanine, tryptophan, or tyrosine.

76. The synthetic peptide of claim 33-63, wherein Xus a sulfur-containing amino acid.

77. The synthetic peptide of claim 76, wherein X4is cysteine or methionine.

78. The synthetic peptide of claim 33-63, wherein X4is an amino acid with a hydroxylcontaining side chain.

79. The synthetic peptide of claim 78, wherein X4is serine or threonine.

80. The synthetic peptide of claim 33-63, wherein X4is an acidic amino acid.

81. The synthetic peptide of claim 80, wherein X4 is aspartic acid or glutamic acid.

82. The synthetic peptide of claim 33-63, wherein X4is a basic amino acid.

83. The synthetic peptide of claim 82, wherein X4is arginine, histidine, or lysine.

84. The synthetic peptide of claim 33-63, wherein X4is an amino acid with an amide- containing sidechain.

85. The synthetic peptide of claim 84, wherein X4 is asparagine or glutamine.

86. The synthetic peptide of claim any one of claims 32-39, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid,glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine.

87. The synthetic peptide of claim 86, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine.

88. The synthetic peptide of claim 87, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

89. The synthetic peptide of any one of claims 32-39 or 86-88, wherein X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, and valine.

90. The synthetic peptide of claim 89, wherein X2is selected from the group consisting of alanine, isoleucine, proline, and valine.

91. The synthetic peptide of claim 90, wherein X2is selected from the group consisting of isoleucine, proline, and valine.

92. The synthetic peptide of any one of claims 32-39 or 86-91, wherein X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

93. The synthetic peptide of claim 92, wherein X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

94. The synthetic peptide of claim 93, wherein X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

95. A synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii)six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 4:PRPPKRXi (SEQ ID NO: 4), wherein Xi is absent or any amino acid, and if Xi is isoleucine and the synthetic peptide is a 15-mer, then Xi is not the C-terminal amino acid.

96. The synthetic peptide of claim 95, consisting essentially of an amino acid sequence of six to thirty consecutive amino acids.

97. The synthetic peptide of claim 95, consisting essentially of an amino acid sequence of six to fifty consecutive amino acids.

98. A synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty), or (ii) six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 4:PRPPKRXi (SEQ ID NO: 4), wherein Xi is absent or any amino acid, and if Xi is isoleucine and the synthetic peptide is a 15-mer, then Xi is not the C-terminal amino acid and / or proline is not the N-terminal amino acid.

99. The synthetic peptide of claim 98, consisting essentially of an amino acid sequence of six to thirty consecutive amino acids.

100. The synthetic peptide of claim 98, consisting essentially of an amino acid sequence of six to fifty consecutive amino acids.

101. The synthetic peptide of any one of claims 95-100, wherein Xi is a charged amino acid.

102. The synthetic peptide of claim 101, wherein Xi is a positively charged amino acid.

103. The synthetic peptide of claim 102, wherein Xi is selected from the group consisting of arginine, histidine, and lysine.

104. The synthetic peptide of claim 101, wherein Xi is a negatively charged amino acid.

105. The synthetic peptide of claim 104, wherein Xi is aspartic acid or glutamic acid.

106. The synthetic peptide of any one of claims 95-100, wherein Xi is an uncharged amino acid.

107. The synthetic peptide of claim 106, wherein Xi is alanine, asparagine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

108. The synthetic peptide of any one of claims 95-100, wherein Xi is an aliphatic amino acid.

109. The synthetic peptide of claim 108, wherein Xi is selected from the group consisting of alanine, glycine, isoleucine, leucine, proline, and valine.

110. The synthetic peptide of claim any one of claims 95-100, wherein Xi is isoleucine.

111. The synthetic peptide of claim 110, wherein the synthetic peptide comprises the amino acid sequence of SEQ ID NO: 5, 6, or 7:PRPPKRI (SEQ ID NO: 5),PRPPKRIL (SEQ ID NO: 6), orPRPPKRILE (SEQ ID NO: 7).

112. The synthetic peptide of any one of claims 95-100, wherein Xi is an aromatic amino acid.

113. The synthetic peptide of claim 112, wherein Xi is phenylalanine, tryptophan, or tyrosine.

114. The synthetic peptide of any one of claims 95-100, wherein Xi is a sulfur-containing amino acid.

115. The synthetic peptide of claim 114, wherein Xi is cysteine or methionine.

116. The synthetic peptide of any one of claims 95-100, wherein Xi is an amino acid with a hydroxyl-containing side chain.

117. The synthetic peptide of claim 116, wherein Xi is serine or threonine.

118. The synthetic peptide of any one of claims 95-100, wherein Xi is an acidic amino acid.

119. The synthetic peptide of claim 118, wherein Xi is aspartic acid or glutamic acid.

120. The synthetic peptide of any one of claims 95-100, wherein Xi is a basic amino acid.

121. The synthetic peptide of claim 120, wherein Xi is arginine, histidine, or lysine.

122. The synthetic peptide of any one of claims 95-100, wherein Xi is an amino acid with an amide-containing sidechain.

123. The synthetic peptide of claim 122, wherein Xi is asparagine or glutamine.

124. The synthetic peptide of any one of claims 95-100, wherein the synthetic peptide has the amino acid sequence of SEQ ID NO: 8, 9, or 10:PRPPKR (SEQ ID NO: 8)PPRPPKR (SEQ ID NO: 9)PPPEHIPPPPRPPKR (SEQ ID NO: 10).

125. A synthetic peptide consisting essentially of an amino acid sequence of seven to ten consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; if Xi is alanine and X2 is valine, then X3 is not proline; if X2 is proline and X3 is arginine, then Xi is not arginine or glutamine; and if X2 is proline and X3 is methionine, then Xi is not histidine.

126. A synthetic peptide consisting essentially of an amino acid sequence of eleven consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine;X4is either absent or any amino acid; and if X2 is proline and X4is not absent, then(i) Xi is not threonine;(ii) X3 is not lysine; and / or(iii) X4 is not serine.

127. A synthetic peptide consisting essentially of an amino acid sequence of twelve consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine;X4is either absent or any amino acid; if X2 is proline and X4is not absent, then(i) Xi is not arginine;(ii) X3 is not threonine; and / or(iii) X4 is not threonine.

128. A synthetic peptide consisting essentially of an amino acid sequence of thirteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; andX4is either absent or any amino acid.

129. A synthetic peptide consisting essentially of an amino acid sequence of fourteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine;X4is either absent or any amino acid; if Xi is alanine and X2 is valine, then X3 is not proline; and if X2 is proline and X4is absent, then:(i) Xi is not arginine; and / or(ii) X3 is not serine.

130. A synthetic peptide consisting essentially of an amino acid sequence of fifteen consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine;X4is either absent or any amino acid; andif X2 is proline and Xns not absent, then:(i) if Xi is arginine, X3 is lysine, and X4 is isoleucine, then X s not the C- terminal amino acid and / or the N-terminal amino acid is not a proline;(ii) if X4 is alanine, then Xi is not proline and / or X3 is not arginine; and(iii) if X4 is proline, then:(a) if Xi is methionine, then X3 is not asparagine; and(b) if Xi is arginine, then X3 is not glycine.

131. A synthetic peptide consisting essentially of an amino acid sequence of (i) sixteen to thirty (sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty -two, twenty -three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty -nine, or thirty) or (ii) sixteen to 50 (sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty -two, twenty- three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3:PX1X2PX3RX4 (SEQ ID NO: 3) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine;X4is either absent or any amino acid; wherein, if the synthetic peptide consists essentially of twenty consecutive amino acids, then the four most C-terminal amino acid residues of the synthetic peptide is not SLSR (SEQ ID NO: 85).

132. The synthetic peptide of claim 131, consisting essentially of an amino acid sequence of sixteen to thirty consecutive amino acids.

133. The synthetic peptide of claim 131, consisting essentially of an amino acid sequence of sixteen to fifty consecutive amino acids.

134. The synthetic peptide of any one of claims 127-133, wherein X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine.

135. The synthetic peptide of claim 134, wherein X2 is selected from the group consisting of alanine, isoleucine, proline, and valine.

136. The synthetic peptide of claim 135, wherein X2 is selected from the group consisting of isoleucine, proline, and valine.

137. The synthetic peptide of any one of claims 1-136, wherein the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a KD of < 1,000 pM.

138. The synthetic peptide of claim 137, wherein the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a KD of < 600 pM.

139. The synthetic peptide of claim 138, wherein the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a Ko of < 300 pM.

140. A synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to fifty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid;X2 is selected from the group consisting of selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine;the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a KD of < 1,000 pM.

141. The synthetic peptide of claim 140, consisting essentially of an amino acid sequence of six to thirty consecutive amino acids.

142. The synthetic peptide of claim 140, consisting essentially of an amino acid sequence of six to fifty consecutive amino acids.

143. The synthetic peptide of any one of claims 140-142, wherein X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine.

144. The synthetic peptide of claim 143, wherein X2 is selected from the group consisting of alanine, isoleucine, proline, and valine.

145. The synthetic peptide of claim 144, wherein X2 is selected from the group consisting of isoleucine, proline, and valine.

146. The synthetic peptide of any one of claims 142-145, consisting essentially of an amino acid sequence of at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen consecutive amino acids.

147. The synthetic peptide of any one of claims 142-145, wherein the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a KD of < 600 pM.

148. The synthetic peptide of claim 147, wherein the synthetic peptide exhibits binding to the SH3-2 domain of NCK1 with a Ko of < 300 pM.

149. The synthetic peptide of any one of claims 1-148, wherein at least one amino acid or two amino acid residues are covalently linked to a chemical moiety not present in a natural amino acid.

150. The synthetic peptide of claim 149, wherein the N-terminal amino acid comprises a modification.

151. The synthetic peptide of claim 150, wherein the N-terminal amino acid is acetylated.

152. The synthetic peptide of any one of claims 1-150, wherein the N-terminal amino acid is H-pyroglutamic acid (H-Pyr).

153. The synthetic peptide of any one of claims 1-152, wherein the C-terminal amino acid comprises a modification.

154. The synthetic peptide of claim 153, wherein the C-terminal amino acid is amidated.

155. The synthetic peptide of claim 153, wherein the C-terminal amino acid comprises an ethyl ami de (NHEt) group.

156. The synthetic peptide of any one of claims 1-155, comprising an amino acid residue (Xo) that is N-terminal to position 1 in SEQ ID NO: 1, 2, 3, or 4.

157. The synthetic peptide of claim 156, wherein Xo selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

158. The synthetic peptide of claim 157, wherein Xo is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

159. A composition comprising the synthetic peptide of any one of claims 1-158 and a salt.

160. The composition of claim 159, wherein the salt is an acetate.

161. The composition of claim 160, wherein the acetate is bis-acetate.

162. The composition of claim 160, wherein the acetate is tri-acetate.

163. A composition comprising a synthetic peptide of any one of claims 1-158, or a composition of any one of claims 159-162, wherein the purity of the synthetic peptide in the composition is at least 95% (e.g., 95%, 96%, 97%, 98%, 99%).

164. A pharmaceutical composition comprising the synthetic peptide of any one of claims 1- 158, or the composition of any one of claims 159-163, and a pharmaceutically acceptable carrier.

165. A pharmaceutical composition comprising a synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to fifty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty-three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, sixto twenty-eight, six to twenty -nine, or six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N- terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine;X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine; andX3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

166. The pharmaceutical composition of claim 165, wherein the pharmaceutical composition consists essentially of an amino acid sequence of six to thirty consecutive amino acids.

167. The pharmaceutical composition of claim 165, wherein the pharmaceutical composition consists essentially of an amino acid sequence of six to fifty consecutive amino acids.

168. The pharmaceutical composition of any one of claims 165-167, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine.

169. The pharmaceutical composition of claim 168, wherein Xi is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.

170. The pharmaceutical composition of any one of claims 165-169, wherein X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine.

171. The pharmaceutical composition of claim 170, wherein X2 is selected from the group consisting of alanine, isoleucine, proline, and valine.

172. The pharmaceutical composition of claim 171, wherein X2 is selected from the group consisting of isoleucine, proline, and valine.

173. The pharmaceutical composition of any one of claims 165-172, wherein X3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

174. The pharmaceutical composition of claim 173, wherein X3 is selected from the group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, and valine.

175. The pharmaceutical composition of any one of claims 165-174, wherein the composition is sterile.

176. The pharmaceutical composition of any one of claims 165-175, wherein the composition is dried (e.g., freeze dried or lyophilized).

177. The pharmaceutical composition of any one of claims 165-175, wherein the composition is an aqueous composition.

178. The pharmaceutical composition of claim 177, wherein the aqueous composition is injectable.

179. The pharmaceutical composition of claim 177 or 178, wherein the concentration of the synthetic peptide is between about 150 mg / mL and about 400 mg / mL.

180. The pharmaceutical composition of claim 179, wherein the concentration of the synthetic peptide is between about 200 mg / mL and about 300 mg / mL.

181. A delivery system comprising (i) delivery device and (ii) a composition of any one of claims 159-163 or a pharmaceutical composition of any one of claims 164-180.

182. The delivery system of claim 181, wherein the delivery device comprises a syringe.

183. A method of modulating the activity of NCK1, the method comprising contacting NCK1 with a synthetic peptide of any one of claims 1-158 or the composition of any one of claims 159- 163, thereby to modulate the activity of NCK1.

184. The method of claim 183, wherein the step of contacting disrupts the interaction between PTP1B and NCK1.

185. A method of modulating the activity of NCK1, the method comprising contacting NCK1 with an agent that disrupts an interaction between PTP1B and NCK1, thereby to modulate the activity of NCK1.

186. The method of claim 185, wherein the agent comprises a peptide.

187. The method of any one of claims 183-186, wherein the step of contacting results in modulating the activity of PTP1B.

188. A method of decreasing body fat mass in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to decrease body fat mass of the subject, the synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid; andX2 is a non-aromatic amino acid.

189. The method of claim 188, wherein the synthetic peptide consists essentially of an amino acid sequence of six to thirty consecutive amino acids.

190. The method of claim 188, wherein the synthetic peptide consists essentially of an amino acid sequence of six to fifty consecutive amino acids.

191. A method of decreasing body fat mass in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceuticalcomposition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to decrease body fat mass of the subject, the synthetic peptide consisting essentially of an amino acid sequence of (i) six to 30 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid; andX2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine.

192. The method of claim 191, wherein the synthetic peptide consists essentially of an amino acid sequence of six to thirty consecutive amino acids.

193. The method of claim 191, wherein the synthetic peptide consists essentially of an amino acid sequence of six to fifty consecutive amino acids.

194. A method of decreasing body fat mass in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide of any one of claims 1- 158, the composition of any one of claims 159-163, or the pharmaceutical composition of any one of claims 164-180, thereby to decrease body fat mass of the subject.

195. A method of treating or preventing obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat obesity in the subject,the synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid; andX2 is a non-aromatic amino acid.

196. The method of claim 195, wherein the synthetic peptide consists essentially of an amino acid sequence of six to thirty consecutive amino acids.

197. The method of claim 195, wherein the synthetic peptide consists essentially of an amino acid sequence of six to fifty consecutive amino acids.

198. A method of treating or preventing obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat or prevent obesity in the subject, the synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39,six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid; andX2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine.

199. The method of claim 198, wherein the synthetic peptide consists essentially of an amino acid sequence of six to thirty consecutive amino acids.

200. The method of claim 198, wherein the synthetic peptide consists essentially of an amino acid sequence of six to fifty consecutive amino acids.

201. A method of treating or preventing obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide of any one of claims 1-144, the composition of any one of claims 145-149, or the pharmaceutical composition of any one of claims 150-165, thereby to treat obesity in the subject.

202. A method of treating or preventing diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat or prevent diabetes in the subject, the synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminalamino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ IDNO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid; andX2 is a non-aromatic amino acid.

203. The method of claim 202, wherein the synthetic peptide consists essentially of an amino acid sequence of six to thirty consecutive amino acids.

204. The method of claim 202, wherein the synthetic peptide of consists essentially of an amino acid sequence of six to fifty consecutive amino acids.

205. A method of treating or preventing diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide or a pharmaceutical composition comprising the synthetic peptide and a pharmaceutically acceptable carrier, thereby to treat or prevent diabetes in the subject, the synthetic peptide consisting essentially of an amino acid sequence of (i) six to thirty (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty-four, six to twenty -five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty-nine, or six to thirty) or (ii) six to 50 (six to fifteen, six to sixteen, six to seventeen, six to eighteen, six to nineteen, six to twenty, six to twenty-one, six to twenty -two, six to twenty -three, six to twenty -four, six to twenty-five, six to twenty-six, six to twenty-seven, six to twenty-eight, six to twenty -nine, six to thirty, six to 31, six to 32, six to 33, six to 34, six to 35, six to 36, six to 37, six to 38, six to 39, six to 40, six to 41, six to 42, six to 43, six to 44, six to 45, six to 46, six to 47, six to 48, six to 49, or six to 50) consecutive amino acids including an N-terminal amino acid and a C-terminal amino acid, wherein the amino acid sequence comprises the amino acid sequence of SEQ ID NO: 2:PX1X2PX3R (SEQ ID NO: 2) whereinXi and X3 are each independently any amino acid; andX2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine, and valine.

206. The method of claim 205, wherein the synthetic peptide consists essentially of an amino acid sequence of six to thirty consecutive amino acids.

207. The method of claim 205, wherein the synthetic peptide consists essentially of an amino acid sequence of six to fifty consecutive amino acids.

208. A method of treating or preventing diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic peptide of any one of claims 1-158, the composition of any one of claims 159-163, or a pharmaceutical composition of any one of claims 164-180, thereby to treat or prevent diabetes in the subject.

209. The method of any one of claims 205-208, wherein the diabetes is type 2 diabetes.

210. The method of any one of claims 191-193, 198-200, or 205-207, wherein X2 is selected from the group consisting of alanine, arginine, isoleucine, leucine, lysine, proline, threonine, tyrosine, and valine.

211. The method of claim 210, wherein X2 is selected from the group consisting of alanine, isoleucine, proline, and valine.

212. The method of claim 211, wherein X2 is selected from the group consisting of isoleucine, proline, and valine.

213. The method of any one of claims 191-193, 198-200, 205-207, or 210-212, consisting essentially of an amino acid sequence of at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen consecutive amino acids.

214. The method of any one of claims 188-213, wherein the subject is a mammal.

215. The method of claim 214, wherein the mammal is a human.

216. The method of any one of claims 188-215, wherein the administration comprises systemic administration.

217. The method of claim 216, wherein the administration comprises subcutaneous administration.

218. The method of any one of claims 188-217, wherein Xi is a charged amino acid.

219. The method of claim 218, wherein Xi is a positively charged amino acid.

220. The method of claim 219, wherein Xi is arginine, histidine, or lysine.

221. The method of claim 218, wherein Xi is a negatively charged amino acid.

222. The method of claim 221, wherein Xi is glutamic acid.

223. The method of any one of claims 188-217, wherein Xi is an uncharged amino acid.

224. The method of claim 223, wherein Xi is a hydrophobic amino acid.

225. The method of claim 223, wherein Xi is selected from the group consisting of alanine, asparagine, and serine.

226. The method of any one of claims 188-190, 194, 195-197, 201, 202-204, 208, or 209, wherein X2 is an uncharged, non-aromatic amino acid.

227. The method of claim 226, wherein X2 is alanine or proline.

228. The method of claim 226, wherein X2 is a hydrophobic, non-aromatic amino acid.

229. The method of claim 228, wherein X2 is alanine.

230. The method of any one of claims 188-190, 194, 195-197, 201, 202-204, 208, or 209, wherein X2 is a charged amino acid.

231. The method of claim 230, wherein X2 is a positively charged amino acid.

232. The method of claim 231, wherein X2 is arginine.

233. The method of any one of claims 188-232, wherein X3 is a charged amino acid.

234. The method of claim 233, wherein X3 is a positively charged amino acid.

235. The method of claim 234, wherein X3 is arginine, histidine, or lysine.

236. The method of claim 235, wherein X3 is a negatively charged amino acid.

237. The method of claim 236, wherein X3 is glutamic acid.

238. The method of any one of claims 188-232, wherein X3 is an uncharged amino acid.

239. The method of claim 238, wherein X3 is selected from the group consisting of alanine, asparagine, cysteine, serine, and tryptophan.

240. The method of claim 238, wherein X3 is a hydrophobic amino acid.

241. The method of claim 240, wherein X3 is selected from the group consisting of alanine, cysteine, and tryptophan.

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