Peptides with anti-inflammatory properties

Abstract

Aspects of the invention relate to peptides having anti-inflammatory activity, compositions containing one or more of the peptides and the use of the peptides to treat conditions associated with excessive inflammation in animals, particularly humans and other mammals.

Description

[0001] Cross-references to related applications

[0002] Pursuant to 35 U.S.SC §119(e), this application claims priority to U.S. Provisional Patent Application Serial No. 62 / 063,909, filed October 14, 2014, the disclosure of which is hereby incorporated herein by reference in its entirety. Technical Field

[0003] Aspects of the present invention relate to peptides having anti-inflammatory activity, compositions containing one or more of said peptides, and the use of said peptides in treating conditions associated with excessive inflammation in animals, particularly humans and other mammals. Background Technology

[0004] Under normal conditions, inflammation is a process that helps animals recover from injury. Acute inflammation is the initial response of tissues to harmful stimuli. It involves a complex, highly regulated process that begins when cells present in the damaged tissue (including macrophages, dendritic cells, histiocytes, Kupffer cells, and mast cells) sense injury-associated molecules and become activated. Upon activation, these cells release inflammatory mediators, such as vasodilators. Vasodilators induce increased blood flow and vascular permeability near the injury. This, in turn, induces increased movement of plasma and leukocytes (including neutrophils and macrophages) from the blood to the damaged tissue. Inflammatory mediators typically degrade rapidly, so acute inflammation requires constant stimulation to persist. Therefore, once the harmful stimulus is removed, acute inflammation ends.

[0005] Various irritants (including, but not limited to, bacteria, viruses, physical damage, chemical damage, cancer, chemotherapy, and radiation therapy) can induce prolonged and excessive inflammation depending on the specific agent and the genetic makeup of the animal exposed to it. This inflammation (referred to as chronic inflammation) is believed to contribute to many common and debilitating diseases, including heart disease, cancer, respiratory diseases, stroke, neurological disorders such as Alzheimer's disease, diabetes, and kidney disease. Chronic inflammation results in the destruction of normal tissue and its replacement by collagen-rich connective tissue. Collagen-rich connective tissue, also known as scar tissue, exhibits reduced tissue function compared to normal tissue. Persistent and prolonged scar tissue formation further leads to fibrosis. Fibrosis is a common symptom of diseases affecting the lungs, skin, liver, heart, and bone marrow, and is a key factor in diseases such as idiopathic pulmonary fibrosis, scleroderma, keloids, cirrhosis, myocardial fibrosis, diabetic nephropathy, spinal dysplasia syndrome, and other conditions.

[0006] Studies of chronic inflammation and fibrosis have indicated that, regardless of the activators and affected tissues, a common network of signaling proteins tends to work together to establish a pro-inflammatory state. This network of signaling proteins includes many different cytokines, cytokine receptors, transcription factors, and microRNAs, including TGFβ, TGFβRII, and miRNA19b.

[0007] Despite growing knowledge about conditions involving excessive inflammation, such as chronic inflammation and fibrosis, treatments for these conditions remain unclear. Many drugs and other substances have been shown to have anti-inflammatory activity, either in vivo or in vitro, but no treatment exists for many complications caused or exacerbated by inflammation. Furthermore, many anti-inflammatory therapies are associated with harmful side effects. Therefore, there is still an urgent need to identify therapeutic agents that reduce inflammation without harmful side effects. Summary of the Invention

[0008] This invention is based in part on the discovery of novel peptides with potent in vitro and in vivo anti-inflammatory activity. It is also based in part on the discovery that the peptides of this invention specifically bind to key functional regions of one or more signaling proteins, particularly pro-inflammatory cytokines, macrophage inhibitory proteins, and histone regulatory proteins. Furthermore, this invention is based in part on the discovery that the peptides of this invention are sufficiently stable in circulation to allow for intravenous administration.

[0009] Therefore, in one aspect, the present invention provides a composition comprising an anti-inflammatory peptide. In some embodiments, the anti-inflammatory peptide is 3 to 24 amino acid residues in length and comprises a striapathic region consisting of alternating hydrophobic and hydrophilic modules. In some embodiments, each hydrophilic module consists of a sequence of one or more (e.g., 1-5, 1-4, 1-3) hydrophilic amino acid residues. In some embodiments, each hydrophobic module consists of a sequence of one or more (e.g., 1-5, 1-4, 1-3) hydrophobic amino acid residues.

[0010] In some embodiments, the banded hydrophilic-reactive region of the anti-inflammatory peptide comprises m hydrophilic modules and n hydrophobic modules, where m and n are positive integers. For example, in some embodiments, the banded hydrophilic-reactive region comprises two hydrophilic modules and two hydrophobic modules (2:2), two hydrophilic modules and three hydrophobic modules (2:3), three hydrophilic modules and two hydrophobic modules (3:2), three hydrophilic modules and three hydrophobic modules (3:3), three hydrophilic modules and four hydrophobic modules (3:4), or four hydrophilic modules and three hydrophobic modules (4:3).

[0011] In some embodiments, the length of the banded affinity region of the anti-inflammatory peptide is at least 5, 6, 7, 8, 9, or 10 amino acid residues. In a preferred embodiment, the length of the banded affinity region is between 7 and 12 amino acid residues. In some embodiments, the banded affinity region constitutes at least 25% of the peptide length. For example, in some embodiments, the banded affinity region constitutes at least 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the peptide length.

[0012] In some implementations, the band-like affinity regions of the anti-inflammatory peptide employ a helical secondary structure. Examples of helical secondary structures include 3 10 - Helices, α-helices, π-helices, and polyproline helices. In other embodiments, the band-like affinity / reluctance regions of the anti-inflammatory peptide employ a β-chain secondary structure. In a preferred embodiment, the band-like affinity / reluctance regions of the anti-inflammatory peptide have an amphiphilic conformation.

[0013] In some embodiments, the anti-inflammatory peptide comprises a banded region having a sequence corresponding to any of the structural formulas disclosed herein (e.g., any of Formulas I-LIII), and is substantially composed of or constitutes the region. In some embodiments, the anti-inflammatory peptide is one of the peptides listed in Tables 3-9. In other embodiments, the anti-inflammatory peptide has at least 70%, 80%, or 90% homology to any of the peptides disclosed in Tables 3-9.

[0014] In some embodiments, the anti-inflammatory peptide binds to at least one signaling protein. In a preferred embodiment, the anti-inflammatory peptide binds to at least one signaling protein with sufficient affinity in vitro and / or in vivo to modulate the activity of the signaling protein. Examples of signaling proteins bound by the anti-inflammatory peptide include proteins that function as pro-inflammatory cytokines, proteins that inhibit macrophage activity, or proteins that regulate histone function. In some embodiments, the anti-inflammatory peptide binds to protein targets selected from the group consisting of: NF-κB class II proteins (e.g., Rel A, Rel B, cRel, NF-κB1, and NF-κB2), TGFβ, Notch receptors (e.g., Notch1), Wnt receptors (e.g., Wnt8R), TRAIL, EGFR, interleukin receptors (e.g., IL6R, IL10R), cyclin-dependent kinases (e.g., CDK6), CD47, SIRP-α, transglutaminases (e.g., TGM2), LEGUMAIN, CD209, FAS, programmed cell death protein 1 (PD-1 / CD279), mitogen-activated protein kinase 7 (MKK7), ribonucleotide reductase (RNR), and histone methyltransferases. In a preferred embodiment, the anti-inflammatory peptide binds to two, three, four, or more of these signaling proteins. For example, in some embodiments, the anti-inflammatory peptide binds to an NF-κB class II protein (e.g., RelB) and at least one other signaling protein that functions as a pro-inflammatory cytokine, an inhibitor of macrophage activity, or a histone function modulator. In a preferred embodiment, the anti-inflammatory peptide binds to the NF-κB class II protein and at least one other protein target with sufficient binding affinity to each target to modulate the in vivo activity of both targets. In a preferred embodiment, the anti-inflammatory peptide binds to the dimerization site of the NF-κB class II protein (e.g., RelB).

[0015] In some implementations, the anti-inflammatory peptide binds to a carrier protein in the blood (e.g., serum albumin).

[0016] In some embodiments, the anti-inflammatory peptide is modified to include, for example, a linker, carbohydrate, lipid, or polymer (e.g., PEG). In some embodiments, a first anti-inflammatory peptide is linked to a second anti-inflammatory peptide to form a polymer, such as a dimer. In some embodiments, the dimer is a homodimer. In other embodiments, the dimer is a heterodimer. In some embodiments, the linker is a peptide linker. In a preferred embodiment, the peptide linker forms a peptide bond with the C-terminus of the first anti-inflammatory peptide and with the N-terminus of the second anti-inflammatory peptide. In some embodiments, the linker is a biodegradable linker. In some embodiments, the linker is a disulfide bond. In some embodiments, the disulfide bond is formed via a pair of cysteine ​​residues (e.g., one cysteine ​​residue from each linked peptide).

[0017] In some embodiments, the anti-inflammatory peptide is linked to a molecule other than another anti-inflammatory peptide. For example, the anti-inflammatory peptide may be linked to a tag or a chemotherapeutic agent. In some embodiments, the linker is a biodegradable linker. In some embodiments, the linker is a disulfide bond (e.g., involving a thiol group of a cysteine ​​residue located at the C-terminus or N-terminus of the anti-inflammatory peptide).

[0018] In another aspect, the present invention provides pharmaceutical compositions comprising an anti-inflammatory peptide and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a single type of anti-inflammatory peptide. In other embodiments, the pharmaceutical composition comprises a combination of two or more anti-inflammatory peptides. In a preferred embodiment, the pharmaceutical composition is substantially free of blood proteins and / or metabolites visible in the blood. In other embodiments, the pharmaceutical composition comprises serum albumin (e.g., human serum albumin). In a preferred embodiment, any serum albumin present in the pharmaceutical composition is recombinantly generated and / or substantially free of other blood proteins and / or metabolites visible in the blood. In some embodiments, the pharmaceutical composition comprises 1 mg to 1000 mg (e.g., 10 to 400 mg, 20 to 300 mg, or about 25 to 250 mg) of the anti-inflammatory peptide.

[0019] In another aspect, the present invention provides a method of treating a subject by administering to a subject a composition comprising an anti-inflammatory peptide (e.g., a pharmaceutical composition). In some embodiments, the subject is an animal, such as a mammal (e.g., a human). In some embodiments, the subject has elevated levels of inflammatory cytokines, is suffering from chronic inflammatory symptoms, or may develop chronic inflammatory symptoms. In some embodiments, chronic inflammatory symptoms may be irritable bowel disease, ulcerative colitis, colitis, Crohn's disease, fibrosis, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, autoimmune diseases, feline or human immunodeficiency virus (FIV or HIV) infection, or cancer. In some embodiments, cancer may be colon cancer, breast cancer, leukemia, lymphoma, ovarian cancer, prostate cancer, liver cancer, lung cancer, testicular cancer, cervical cancer, bladder cancer, endometrial cancer, kidney cancer, melanoma, or thyroid cancer or brain cancer. In some embodiments, the composition is administered in combination with a chemotherapy agent, an immunotherapy agent, and / or radiotherapy.

[0020] These and other features and advantages of the compositions and methods of the present invention will be set forth in the following description and the appended claims, or will become more apparent from the description and claims themselves. For example, suitable anti-inflammatory peptides can be identified by using the structural algorithms described herein. Furthermore, the features and advantages of the compositions and methods will become apparent from practice of the methods or from the description. Attached Figure Description

[0021] Figure 1 A structural model of human RelB, a class II NF-κB protein, was depicted.

[0022] Figure 2 A structural model of human RelB bound to RP-182 was depicted.

[0023] Figure 3 A structural model of human RelB bound to RP-166 was depicted.

[0024] Figure 4 A structural model of human RelB bound to RP-113 was depicted.

[0025] Figure 5 A structural model of the human RelB bound to RP-387 was depicted.

[0026] Figure 6 A structural model of the human RelB associated with RP-289 was depicted.

[0027] Figure 7 A structural model of human RelB bound by NF-Contr2 is described.

[0028] Figure 8 A structural model of human RelB bound by NF-Contr3 is depicted.

[0029] Figure 9 Structural models of peptides RP-182, RP-166, RP-113, and RP-289 were depicted, with each model showing the correlation between polar and nonpolar facial curvature and the helix formed by the peptide.

[0030] Figure 10 Structural models of peptides RP-387, NF-Contr2, and NF-Contr3 were depicted, with each model showing both polar and nonpolar amino acid residues. Facial curvature associated with the helix formed by RP-387 was also shown.

[0031] Figure 11 A structural model of the binding bag of the RelB dimer domain is depicted.

[0032] Figure 12 A structural model of the binding bag of the RelB dimer domain bound to RP-183 is depicted.

[0033] Figure 13 A structural model of the histone methyltransferase bound by RP-182 was depicted.

[0034] Figure 14 The structural model of CD47 dimer (left figure) and CD47 dimer bound to RP-183 is depicted.

[0035] Figure 15 The structural model of SIRP-α dimer (left figure) and SIRP-α dimer bound to RP-183 is depicted.

[0036] Figure 16 A structural model of CD206 (right side) combined with CD206 (left side) and RP-182 is depicted.

[0037] Figure 17 The structural model of TGM2 (right side) combined with RP-182 is depicted.

[0038] Figure 18 A structural model of human serum albumin bound by RP-183 was depicted.

[0039] Figure 19 The images show PD-1-stained tumor cells from p53 / KRAS mice treated with the medium alone (left panel) or with RP-182 (right panel). PD-1 expression was reduced in RP-182-treated mice.

[0040] Figure 20The images show PD-L1-stained (left panel) and PD-L2-stained (right panel) tumor cells from p53 / KRAS mice treated with the medium alone (top panel in each set) or with RP-182 (bottom panel in each set). PD-L1 and PD-L2 expression was reduced in RP-182-treated mice.

[0041] Figure 21 The tumor volume of MDA-MB-231 over time is shown in four mouse groups. Group 1: mediator; Group 2: gemcitabine-treated; Group 3: RP-182-treated; Group 4: RP-182 + gemcitabine-treated.

[0042] Figure 22 The C42B tumor volume over time is shown in four mouse groups. Group 1: mediator; Group 2: docetaxel treatment; Group 3: RP-182 treatment; Group 4: RP-182 + docetaxel treatment. Detailed Implementation

[0043] The following description provides specific details to provide a full understanding of the invention. That is, to avoid obscuring aspects of the anti-inflammatory peptides and related methods of treating subjects, well-known structures, materials, processes, techniques, and operations are not shown or described in detail. Furthermore, those skilled in the art will understand that the anti-inflammatory peptides and related methods of treating subjects can be implemented and used without these specific details. In fact, the anti-inflammatory peptides and methods can be implemented by modifying the described peptides, compositions, and methods, and can be used in conjunction with other treatments, devices, and techniques conventionally used in industry.

[0044] As discussed above, the invention disclosed herein relates to immunomodulatory peptides, particularly peptides with immunosuppressive properties, and methods for administering such immunomodulatory peptides to subjects (particularly subjects suffering from or at risk of developing a medical condition associated with persistent inflammation).

[0045] This invention provides anti-inflammatory peptides, sometimes referred to as "RP peptides," that satisfy the requirements of the structural algorithm described below. This invention also provides anti-inflammatory peptides that share minimal homology with any of the exemplary RP peptides disclosed herein. Therefore, the peptides or polypeptides of this invention are anti-inflammatory peptides that satisfy the structural algorithm described below or that share minimal homology with any of the exemplary RP peptides disclosed herein (e.g., in Tables 3-9).

[0046] The terms “peptide” and “polypeptide” are used synonymously in this document and refer to polymers composed of amino acid residues.

[0047] As used herein, the term "amino acid residue" refers to any naturally occurring amino acid (in L or D form), a non-naturally occurring amino acid, or an amino acid analogue (such as a peptide monomer).

[0048] The “length” of a polypeptide is the number of amino acid residues that make up the polypeptide, linked end-to-end, excluding any non-peptide linkers and / or modifications that the polypeptide may contain.

[0049] As used herein, the term "banded hydrophobic / hydrophobic region" refers to alternating sequences of hydrophobic and hydrophilic modules. A "hydrophobic module" is composed of a peptide sequence consisting of one to five hydrophobic amino acid residues. Similarly, a hydrophilic module is composed of a peptide sequence consisting of one to five hydrophilic amino acid residues.

[0050] Hydrophobic amino acid residues are characterized by functional groups (“side chains”) that are predominantly nonpolar in chemical properties. Such hydrophobic amino acid residues can be naturally occurring (L or D form) or non-naturally occurring. Optionally, hydrophobic amino acid residues can be amino acid mimics characterized by functional groups (“side chains”) that are predominantly nonpolar in chemical properties. Conversely, hydrophilic amino acid residues are characterized by functional groups (“side chains”) that are predominantly polar (charged or uncharged) in chemical properties. Such hydrophilic amino acid residues can be naturally occurring (L or D form) or non-naturally occurring. Optionally, hydrophilic amino acid residues can be amino acid mimics characterized by functional groups (“side chains”) that are predominantly polar (charged or uncharged) in chemical properties. Examples of hydrophilic and hydrophobic amino acid residues are shown in Table 1 below. Suitable non-naturally occurring amino acid residues and amino acid mimics are known in the art. See, for example, Liang et al., (2013), “An Index for Characterization of Natural and Non-Natural Amino Acids for Peptidomimetics,” PLoS ONE 8(7):e67844.

[0051] Although most amino acid residues can be considered hydrophobic or hydrophilic, a few can behave differently depending on their context. For example, glycine, proline, and / or cysteine ​​can sometimes act as hydrophilic amino acid residues due to their relatively weak nonpolarity. Conversely, histidine and arginine can sometimes act as hydrophobic amino acid residues due to their large, slightly hydrophobic side chains.

[0052] Table 1: Hydrophobic and Hydrophilic Amino Acid Residues

[0053] Arginine Tryptophan Histidine Phenylalanine Lysine Tyrosine Aspartic acid Isoleucine glutamic acid Leucine Asparagine Valine glutamine Methionine Pyrrolidone Cysteine threonine Serine alanine proline glycine selenocysteine N-formylmethionine Ortholeucine valine

[0054] As used herein, the term "anti-inflammatory property" refers to any property of a peptide that can be evaluated in a computer, in vitro, and / or in vivo, which reduces or inhibits, or is intended to reduce or inhibit, pro-inflammatory signaling mediated by protein targets and / or reduce or inhibit inflammation in a subject.

[0055] Structure Algorithm

[0056] In its most basic form, the structural algorithm requires the anti-inflammatory peptide to have the following characteristics:

[0057] The length ranges from 3 to 24 amino acid residues;

[0058] A banded region comprising at least 25% of the polypeptide length; and

[0059] At least one anti-inflammatory property.

[0060] Antiinflammatory peptides and / or their banded affinity regions can have a length of more than 3 amino acid residues and / or less than 24 amino acid residues. Therefore, the required length of the peptide can be, for example, 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 4 to 20, 4 to 18, 4 to 16, 4 to 14, 4 to 12, 5 to 20, 5 to 18, 5 to 16, 5 to 14, 5 to 12, 6 to 20, 6 to 18, 6 to 16, 6 to 14, 6 to 12, 7 to 20, 7 to 18, 7 to 16, 7 to 14, or in some embodiments, 7 to 12 amino acid residues. For antiinflammatory peptides longer than 12 amino acid residues, it is advantageous to design kinks in the secondary structure (e.g., such as those generated via proline residues) so that the peptide has a banded affinity region of 12 or fewer amino acid residues. The banded affinity regions of anti-inflammatory peptides can constitute at least 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the peptide length.

[0061] Anti-inflammatory peptides may have a banded region comprising at least two hydrophobic modules and one or more (e.g., two or three) hydrophilic modules. Optionally, anti-inflammatory peptides may have a banded region comprising at least three hydrophobic modules and two or more (e.g., three or four) hydrophilic modules; a banded region comprising at least two hydrophobic modules and one or more (e.g., two or three) hydrophilic modules; or a banded region comprising at least three hydrophilic modules and two or more (e.g., three or four) hydrophobic modules.

[0062] As discussed above, the banded hydrophilic regions consist of alternating hydrophilic (X) regions. m ) module and hydrophobicity (Yn ) Modules. In this context, subscripts m and n are positive integers that identify different modules. Each X m The module is based on formula X ma -X mb -X mc -X md -X me The sequence composition. X ma Select the group consisting of naturally occurring hydrophilic amino acids, non-naturally occurring hydrophilic amino acids, and hydrophilic amino acid mimics; and X mb X mc X md and X me Each Y is an individual group consisting of naturally occurring hydrophilic amino acids, non-naturally occurring hydrophilic amino acids, and hydrophilic amino acid mimics. n The module is based on formula Y na -Y nb -Y nc -Y nd -Y ne The sequence composition. Y na Select the group consisting of naturally occurring hydrophobic amino acids, non-naturally occurring hydrophobic amino acids, and hydrophobic amino acid mimics; Y nb Y nc Y nd and Y ne A group consisting of naturally occurring hydrophobic amino acids, non-naturally occurring hydrophobic amino acids, and hydrophobic amino acid mimics, each of which is absent individually or selected separately.

[0063] In some anti-inflammatory peptides, each X m The module is based on formula X ma -X mb -X mc -X md or X ma -X mb -X mc The sequence composition. Similarly, in some anti-inflammatory peptides, each Y n The module is based on formula Y na -Y nb -Y nc -Y nd Or Y na -Y nb -Y nc The sequence composition.

[0064] Anti-inflammatory peptides may contain banded affinity regions corresponding to formulas selected from the group consisting of:

[0065] Y 1a -Y1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula I);

[0066] Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c -X 2a -Y 3a -X 3a (Formula II);

[0067] X 2a -Y 3a -X 3a -Y 1b -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula III);

[0068] X 1a -X 1b -X 1c -Y 2a -X 2a -X 2b -X 2c (Formula IV);

[0069] Y 1a -X 1a -X 1b -X 1c -Y 2a -X 2a -X 2b -X 2c -Y 3a -X 3a (Formula V);

[0070] X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b (Formula VI);

[0071] Y 1a -X 1a -X 1b -Y 2a -Y 2b -X2a -X 2b -Y 3a (Formula VII);

[0072] Y 1a -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a -Y 3b -X 3a (Formula VIII);

[0073] Y 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a -Y 3b (Formula IX);

[0074] Y 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a -X 3a (Formula X);

[0075] X 1a -Y 1a -X 2a -X 2b -Y 2a -Y 2b -X 3a -X 3b -Y 3a -Y 3b (Formula XI);

[0076] X 1a -Y 1a -Y 1b -X 2a -X 2b -Y 2a -Y 2b -X 3a -X 3b -Y 3a (Formula XII);

[0077] Y 1a-X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -X 2c -Y 3a -Y 3b (Formula XIII);

[0078] X 1a -X 1b -X 1c -Y 1a -Y 1b -X 2a -X 2b -Y 2a -Y 2b -Y 2c (Formula XIV);

[0079] Y 1a -Y 1b -Y 1c -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -X 2c (Formula XV);

[0080] Y 1a -Y 1b -X 1a -X 1b -X 1c -Y 2a -Y 2b -X 2a -X 2b -Y 3a (Formula XVI);

[0081] Y 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b (Formula XVII);

[0082] X 1a -Y 1a -Y 1b -X 2a -X 2b -Y 2a -Y 2b -X 3a (Formula XVIII);

[0083] Y1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b -X 2a -Y 3a -Y 3b -X 3a (Formula XIX);

[0084] X 1a -Y 1a -Y 1b -X 2a -Y 2a -Y 2b -X 3a -X 3b -Y 3a -Y 3b (Formula XX);

[0085] Y 1a -Y 1b -X 1a -X 1b -Y 2a -X 2a -X 2b -Y 3a -Y 3b (Formula XXI);

[0086] X 1a -Y 1a -Y 1b -X 2a -X 2b -X 2c -Y 2a -X 3a -Y 3a -Y 3b (Formula XXII);

[0087] Y 1a -Y 1b -X 1a -Y 2a -X 2a -X 2b -X 2c -Y 3a -Y 3b -X 3a (Formula XXIII);

[0088] X 1a -X 1b -Y 1b -X 2a -Y 2a -X 3a -X 3b(Formula XXIV);

[0089] Y 1a -Y 1b -Y 1c -X 1a -X 1b -Y 2a -X 2a -Y 3a -X 3a -X 3b (Formula XXV);

[0090] X 1a -X 1b -Y 1a -X 2a -Y 2a -X 3a -X 3b -Y 3a -Y 3b -Y 3c (Formula XXVI);

[0091] X 1a -X 1b -X 1c -Y 1a -Y 1b -Y 1c (Formula XXVII);

[0092] X 1a -X 1b -X 1c -X 1d -Y 1a -Y 1b -Y 1c -Y 1d (Formula XXVIII);

[0093] Y 1a -X 1a -X 1b -X 1c -X 1d -Y 2a -Y 2b -Y 2c -Y 2d -X 2a (Formula XXIX);

[0094] X 1a -X 1b -X 1c -X 1d -X 1e -Y 1a -Y 1b -Y 1c -Y 1d-Y 1e (Formula XXX);

[0095] Y 1a -Y 1b -X 1a -X 1b -X 1c -Y 2a -Y 2b -Y 2c -X 2a -X 2b (Formula XXXI);

[0096] X 1a -Y 1a -X 2a -Y 2a -X 3a -X 3b -X 3c -Y 3a -Y 3b -Y 3c (Formula XXXII);

[0097] Y 1a -Y 1b -Y 1c -X 1a -X 1b -X 1c (Formula XXXIII);

[0098] Y 1a -Y 1b -Y 1c -Y 1d -X 1a -X 1b -X 1c -X 1d (Formula XXXIV);

[0099] X 1a -Y 1a -Y 1b -Y 1c -Y 1d -X 2a -X 2b -X 2c -X 2d -Y 2a (Formula XXXV);

[0100] Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 1a -X 1b -X 1c-X 1d -X 1e (Formula XXXVI);

[0101] X 1a -X 1b -Y 1a -Y 1b -Y 1c -X 2a -X 2b -X 2c -Y 2a -Y 2b (Formula XXXVII);

[0102] Y 1a -Y 1b -Y 1c -X 1a -X 1a -X 1c -Y 2a -X 2a -Y 3a -X 3a (Formula XXXVIII);

[0103] Y 1a -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a (Formula XXXIX);

[0104] Y 1a -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a -Y 2b -Y 2c -Y 2d (Formula XL);

[0105] Y 1a -Y 1b -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a -Y 2b -Y 2c (Formula XLI);

[0106] Y 1a -Y 1b -Y 1c -X 1a-X 1b -X 1c -X 1d -X 1e -Y 2a -Y 2b (Formula XLII);

[0107] Y 1a -Y 1b -Y 1c -Y 1e -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a (Formula XLIII);

[0108] X 1a -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a (Formula XLIV);

[0109] X 1a -Y 1a -Y 1b -Y 1c -Y 1d -Y 1c -X 2a -X 2b -X 2c -X 2d (Formula XLV);

[0110] X 1a -X 1b -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a -X 2b -X 2c (Formula XLVI);

[0111] X 1a -X 1b -X 1c -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a X 2b (Formula XLVII);

[0112] X1a -X 1b -X 1c -X 1d -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a (Formula XLVIII);

[0113] Y 1a -X 1a -Y 2a -X 2a -Y 3a -X 3a (Formula XLIX);

[0114] Y 1a -Y 1b -X 1a -Y 2a -Y 2b -X 2a -Y 3a -Y 3b -X 3a -Y 4a (Formula L);

[0115] X 1a -X 1b -Y 1a -Y 1b -X 2a -Y 2a -Y 2b -Y 2c -Y 2d (Formula LI);

[0116] Y 1a -Y 1b -Y 1c -Y 1d -X 1a -Y 2a -Y 2b -X 2a -X 2b (Formula LII);

[0117] Y 1a -Y 1b -X 1b -Y 2a -Y 2b -Y 2c -X 2b -Y 3a -X 3a -Y 4a (Formula LIII); and

[0118] Y 1a -X 1a -Y 2a -X 2a -Y 3a -Y 3b -Y 3c -X 3a -Y 4a -Y 4b (Formula LIV).

[0119] Typically, the banded region (or portion thereof) of an anti-inflammatory peptide will have an amphiphilic conformation (e.g., under physiological conditions). To account for amphiphilicity, the banded region (or portion thereof) does not necessarily need to always be in an amphiphilic conformation. Rather, it is sufficient for the amphiphilic conformation to be present for at least 50%, 60%, 70%, 80%, or more of a duration, or when the anti-inflammatory peptide binds to target molecules such as NF-κB class II proteins (e.g., Rel B). Generally, the amphiphilic conformation will be associated with a specific secondary structure such as a helical structure. Therefore, the banded region (or portion thereof) of an anti-inflammatory peptide may have an amphiphilic conformation. 10 - Helical conformation, amphiphilic α-helical conformation, amphiphilic π-helical conformation, or amphiphilic polyproline helical conformation. Optionally, the banded affinity region (or a portion thereof) of the anti-inflammatory peptide may have an amphiphilic β-chain conformation.

[0120] For those containing or having amphiphilic helical conformations (e.g., 3... 10 An anti-inflammatory peptide comprising a banded region of affinity or reluctance (either a π-helical, α-helical, or polyproline helical conformation), wherein the hydrophobic surface (“side”) may have a facial curvature of at least 100°. In some embodiments, the facial curvature of the hydrophobic surface or side is at least 125°, 150°, 175°, 200°, 225°, 250°, 275°, or 300°.

[0121] In some embodiments, the anti-inflammatory peptide has a banded affinity-reluctance region containing a relatively large hydrophobic volume. Therefore, the banded affinity-reluctance region can optimally comprise hydrophobic amino acid residues having a total side chain volume of at least 600 cubic angstroms. In some embodiments, the hydrophobic amino acid residues in the banded affinity-reluctance region have a hydrophobic side chain volume of at least 650, 700, 750, 800, 850, 900, 950, 1000, or greater cubic angstroms. Optionally or additionally, the banded affinity-reluctance region may be characterized by the ratio of the sum of the side chain volumes of the hydrophobic amino acid residues to the sum of the side chain volumes of the hydrophilic amino acid residues, wherein said ratio is at least 0.75 or higher. For example, the ratio can be at least 0.8, 0.85, 0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 or greater.

[0122] Due to the ideality of banded affinity regions with relatively large hydrophobic side chain volumes, it is generally preferred to include one or more (e.g., 2, 3, 4, 5 or more) large hydrophobic amino acid residues within the sequence of the banded affinity region. Conversely, it is generally preferred to have two or fewer (e.g., 1 or 0) small hydrophobic amino acid residues within the sequence of the banded affinity region. Examples of large hydrophobic amino acid residues include tryptophan, phenylalanine, and tyrosine. Additionally, in some cases, histidine or arginine can be considered as large hydrophobic amino acid residues. Examples of small hydrophobic residues include glycine, alanine, serine, cysteine, valine, threonine, and proline. Therefore, anti-inflammatory peptides can have banded affinity regions containing one or more (e.g., 2, 3, 4, 5 or more) hydrophobic residues selected from the group consisting of tryptophan, phenylalanine, and tyrosine. Optionally, the anti-inflammatory peptide may have a banded affinity / reluctance region comprising one or more (e.g., 2, 3, 4, 5 or more) hydrophobic residues selected from (i) the group consisting of tryptophan, phenylalanine, tyrosine and histidine, or (ii) the group consisting of tryptophan, phenylalanine, tyrosine and arginine. In some embodiments, the anti-inflammatory peptide has a banded affinity / reluctance region comprising two or fewer (e.g., 1 or 0) hydrophobic residues selected from the group consisting of glycine, alanine, serine, cysteine, valine, threonine, and proline. Optionally, the anti-inflammatory peptide has a banded affinity / reluctance region comprising no more than one hydrophobic residue selected from the group consisting of glycine, alanine, serine, cysteine, valine, threonine, and proline. In other alternatives, the anti-inflammatory peptide has a banded affinity region that does not contain glycine residues, alanine residues, serine residues, cysteine ​​residues, valine residues, threonine residues, and / or proline residues.

[0123] Preferably, the anti-inflammatory peptide has a banded affinity region characterized by a moderate level of cationicity (i.e., a banded affinity region without an excessive number of amino acid residues with positively charged side chains). Examples of amino acid residues with positively charged side chain groups (ensuring physiological conditions) include lysine, typically arginine, and sometimes histidine. Examples of amino acid residues with negatively charged side chains (ensuring physiological conditions) include aspartic acid and glutamic acid. Examples of hydrophilic amino acid residues with uncharged side chains (ensuring physiological conditions) include asparagine and glutamine. Thus, the anti-inflammatory peptide may have a banded affinity region containing five or fewer (e.g., 4, 3, 2) lysine residues. Optionally, the anti-inflammatory peptide may have a banded affinity region containing five or fewer (e.g., 4, 3, 2) amino acid residues selected from the group consisting of lysine and arginine. In other alternatives, the anti-inflammatory peptide may have a banded affinity region comprising five or fewer (e.g., 4, 3, 2) amino acid residues selected from the group consisting of lysine, arginine, and histidine. For an anti-inflammatory peptide having a banded affinity region comprising one or more (e.g., two or more) positively charged amino acid residues, it may be advantageous to also have a banded affinity region comprising some negatively charged or polar, uncharged amino acid residues. For example, the anti-inflammatory peptide may have a banded affinity region comprising both positively charged and negatively charged amino acid residues such that the net charge on the peptide does not exceed +2 or +1 (e.g., the number of positively charged amino acid residues does not exceed one or two negatively charged amino acid residues). Alternatively, the anti-inflammatory peptide may have a banded affinity region comprising both positively charged and polar, uncharged amino acid residues such that the net charge on the peptide does not exceed +2 or +1 (e.g., the number of positively charged amino acid residues does not exceed one or two). In other alternatives, anti-inflammatory peptides may have banded affinity regions comprising positively charged amino acid residues, negatively charged amino acid residues, and hydrophilic uncharged amino acid residues, such that the net charge on the peptide does not exceed +2.

[0124] To avoid undesirable interactions between RP peptides and other molecules (whether another RP peptide, metal ions, etc.), limiting the number of certain types of amino acid residues in the polypeptide can be advantageous. For example, because cysteine ​​residues form disulfide bonds under certain conditions (e.g., oxidative environments), it can be appropriate to limit the number of cysteine ​​residues in the polypeptides of the present invention to no more than one or two, or even none. Because histidine residues chelate metals under certain conditions (e.g., alkaline environments), it can be appropriate to limit the number of histidine residues in the polypeptides of the present invention to no more than one or two, or even none. Additionally, because proline tends to introduce kinks into secondary structural elements (e.g., α-helices and β-chains), it can be appropriate to exclude proline residues from the banded affinity / reluctance regions of the polypeptides of the present invention or limit their number to no more than one.

[0125] Class I peptides

[0126] The anti-inflammatory peptide of the present invention can be a class I peptide. A class I peptide comprises a banded region containing a sequence selected from the group defined by formula I, and is substantially composed of or consists of said region:

[0127] Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula I).

[0128] amino acid residue Y in Formula I 1a Y 1b Y 1c Y 2a Y 2b and Y 2c Each of the following can be selected from the group consisting of: Phe (F), Trp (W), Tyr (Y), His (H), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In some embodiments, amino acid residue Y in Formula I... 1a Y 1b Y 1c Y 2a Y 2b and Y 2c At least 3, 4, 5, or 6 of the amino acid residues in Formula I are selected from the group consisting of: Phe (F), Trp (W), Tyr (Y), His (H), and Leu (L). In some embodiments, amino acid residue Y in Formula I... 1a Y 1b Y1c Y 2a Y 2b and Y 2c At least 3, 4, 5, or 6 of the amino acid residues in Formula I are selected from the group consisting of: Phe (F), Trp (W), and Tyr (Y). In some embodiments, amino acid residue Y in Formula I... 1a Y 1b Y 1c Y 2a Y 2b and Y 2c Less than two (and in some embodiments, one or none) of the following groups are selected: Pro(P), Thr(T), Ser(S), Ala(A), and Gly(G).

[0129] Module Y in Equation I 1a -Y 1b -Y 1c Sequences can be selected from groups consisting of: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III). Optionally, module Y in Equation I... 1a -Y 1b -Y 1c It can have sequences selected from the group consisting of Pro-Pro-Pro (PPP), Thr-Thr-Thr (TTT), and Ala-Ala-Ala (AAA). In some embodiments, module Y in Formula I 1a -Y 1b -Y 1cA sequence having a group consisting of the following: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY) and combinations thereof (e.g., Phe-Phe-Trp (FFW), Phe-Trp-Trp (FWW), Trp-Phe-Trp (WFW), Trp-Trp-Phe (WWF), Phe-Phe-Tyr (FFY), Phe-Tyr-Tyr (FYY), Tyr-Phe-Tyr (YFY)). ), Tyr-Tyr-Phe(YYF), Trp-Trp-Tyr(WWY), Trp-Tyr-Tyr(WYY), Tyr-Trp-Tyr(YWY), Tyr-Tyr-Trp(YYW), Phe-Trp- Tyr(FWY), Phe-Tyr-Trp(FYW), Trp-Phe-Tyr(WFY), Trp-Tyr-Phe(WYF), Tyr-Trp-Phe(YWF) or Tyr-Phe-Trp(YFW)).

[0130] Module Y in Equation I 2a -Y 2b -Y 2c Sequences can be selected from groups consisting of: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III). Optionally, module Y in Equation I... 2a -Y 2b -Y 2c It can have sequences selected from the group consisting of Pro-Pro-Pro (PPP), Thr-Thr-Thr (TTT), and Ala-Ala-Ala (AAA). In some embodiments, module Y in Formula I 2a -Y 2b -Y 2cA sequence having a group consisting of the following: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY) and combinations thereof (e.g., Phe-Phe-Trp (FFW), Phe-Trp-Trp (FWW), Trp-Phe-Trp (WFW), Trp-Trp-Phe (WWF), Phe-Phe-Tyr (FFY), Phe-Tyr-Tyr (FYY), Tyr-Phe-Tyr (YFY)). ), Tyr-Tyr-Phe(YYF), Trp-Trp-Tyr(WWY), Trp-Tyr-Tyr(WYY), Tyr-Trp-Tyr(YWY), Tyr-Tyr-Trp(YYW), Phe-Trp- Tyr(FWY), Phe-Tyr-Trp(FYW), Trp-Phe-Tyr(WFY), Trp-Tyr-Phe(WYF), Tyr-Trp-Phe(YWF) or Tyr-Phe-Trp(YFW)).

[0131] Therefore, class I anti-inflammatory peptides may comprise banded regions having sequences selected from the group consisting of, substantially composed of, or composed of, said regions: FFF-X 1a -FFF(SEQ ID NO:1), WWW-X 1a -WWW(SEQ ID NO:2), YYY-X 1a -YYY (SEQ ID NO:3) and combinations thereof. Optionally, class I anti-inflammatory peptides may comprise banded affinity regions having sequences selected from the group consisting of, substantially consisting of, or consisting of, said regions: LLL-X 1a -LLL(SEQ ID NO:4), CCC-X 1a -CCC(SEQ ID NO:5), MMM-X 1a -MMM(SEQ ID NO:6), VVV-X 1a -VVV (SEQ ID NO:7) and III-X 1a -III (SEQ ID NO:8). In this type of peptide, X 1a You can choose a group consisting of Arg(R), His(H), and Lys(K); or X 1a You can choose a group consisting of Glu(E), Gln(Q), Asn(N), and Asp(D).

[0132] Class I anti-inflammatory peptides may comprise banded regions of sequences having a sequence selected from the group defined by Formula II or the group defined by Formula III, substantially consisting of or consisting of said regions:

[0133] Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c -X 2a -Y 3a -X 3a (Formula II);

[0134] X 2a -Y 3a -X 3a -Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula III)

[0135] Y as defined by Equations II and III 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c The sequence can be any sequence described by the above combined formula I. X in formulas II and III 2a and X 3a Each of the following groups can be selected individually: Arg(R), His(H), Lys(K), Glu(E), Gln(Q), Asn(N), and Asp(D). Optionally, X in Equations II and III... 2a and X 3a Each can be individually selected from the group consisting of Arg(R), His(H), and Lys(K). In other alternatives, X in Equations II and III... 2a and X 3a Each can be individually selected from the group consisting of Arg(R), His(H), Lys(K), and Gln(Q). In other alternatives, X in Equations II and III... 2a and X 3a Each of the following can be individually selected from the group consisting of Glu(E), Gln(Q), Asn(N), and Asp(D). In other alternatives, X in Equations II and III... 2aThe group consisting of Arg(R), His(H), and Lys(K) can be freely chosen, and X in Equations II and III... 3a The glutamate can be selected from the group consisting of Glu (E), Gln (Q), Asn (N), and Asp (D). Y3a in Formulas II and III can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), and Ile (I). In some embodiments, Y3a in Formulas II and III is selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L).

[0136] Module X in Equations II and III 2a -Y 3a -X 3a Can be selected from the group consisting of: EFQ, EFE, EFN, EFD, NFQ, NFE, NFN, NFD, QFQ, QFE, QFN, QFD, DFQ, DFE, DFN, DFD, E WQ, EWE, EWN, EWD, NWQ, NWE, NWN, NWD, QWQ, QWE, QWN, QWD, DWQ, DWE, DWN, DWD, EYQ, EYE, EFN, EY D, NYQ, NYE, NYN, NYD, QYQ, QYE, QYN, QYD, DYQ, DYE, DYN, DYD, ELQ, ELE, ELN, ELD, NLQ, NLE, NLN , NLD, QLQ, QLE, QLN, QLD, DLQ, DLE, DLN, DLD, RFR, RFQ, RFE, RFN, RFD, RWR, RWQ, RWE, RWN, and RWD.

[0137] Class I anti-inflammatory peptides may comprise banded affinity regions, substantially composed of or consisting of said regions, said regions comprising sequences selected from the group consisting of sequences listed in Table 3, substantially composed of or consisting of said sequences, such as RP394, RP108-RP123, RP125-131, RP133, RP135-RP141, RP143-RP146, RP148-RP150, RP152-RP165, RP179, RP395, RP211, RP230, RP232, RP258, RP267, RP268, RP271, RP273, RP280-281, and RP287 (i.e., SEQ ID NO: 33-98, respectively). In some embodiments, the class I anti-inflammatory peptide may comprise a banded affinity region, substantially composed of or consisting of said region, said region comprising a sequence selected from the group consisting of said sequences, substantially composed of or consisting of said sequences, said sequences consisting of said sequences: RP113 (SEQ ID NO:39), RP118 (SEQ ID NO:44), and RP394 (SEQ ID NO:33).

[0138] Class II polypeptides

[0139] The anti-inflammatory peptide of the present invention can be a class II peptide. A class II anti-inflammatory peptide can comprise a banded region containing a sequence selected from the group defined by formula VII, substantially consisting of or consisting of said region:

[0140] Y 1a -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a (Formula VII)

[0141] amino acid residue Y in formula VII 2a The following groups can be selected: Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In some embodiments, amino acid residue Y in Formula VII... 2a The following groups are selected: Phe (F), Trp (W), and Tyr (Y). Optionally, amino acid residues Y in Formula VII... 2aYou can choose from the following groups: Leu(L), Cys(C), Met(M), Val(V), Ile(I).

[0142] amino acid residue Y in formula VII 2b The following groups can be selected: Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In some embodiments, amino acid residue Y in Formula VII... 2b The following groups are selected: Phe (F), Trp (W), and Tyr (Y). Optionally, amino acid residues Y in Formula VII... 2b You can choose from the following groups: Leu(L), Cys(C), Met(M), Val(V), Ile(I).

[0143] amino acid residue X in formula VII 1b The following groups can be selected: Arg(R), Lys(K), and His(H). Optionally, amino acid residue X in formula VII... 1b You can choose from the following groups: Asn(N), Gln(Q), Asp(D), and Glu(E).

[0144] amino acid residue X in formula VII 2a The following groups can be selected: Arg(R), Lys(K), and His(H). Optionally, amino acid residue X... 2a You can choose from the following groups: Asn(N), Gln(Q), Asp(D), and Glu(E).

[0145] Sequence X in Equation VII 1b -Y 2a -Y 2b -X 2aThe following groups can be selected: Lys-Phe-Phe-Lys (KFFK; SEQ ID NO:386), Lys-Trp-Trp-Lys (KWWK; SEQ ID NO:387), Lys-Tyr-Try-Lys (KYYK; SEQ ID NO:388), Lys-Phe-Trp-Lys (KFWK; SEQ ID NO:389), Lys-Trp-Phe-Lys (KWFK; SEQ ID NO:390), Lys-Phe-Tyr-Lys (KFYK; SEQ ID NO:391), Lys-Tyr-Phe-Lys (KYFK; SEQ ID NO:392), Lys-Trp-Tyr-Lys (KWYK; SEQ ID NO:393), and Lys-Tyr-Trp-Lys (KYWK; SEQ ID NO:393). NO:394). Optionally, the sequence X in equation VII 1b -Y 2a -Y 2b -X 2a The following groups can be selected: Arg-Phe-Phe-Arg (RFFR; SEQ ID NO:395), Arg-Trp-Trp-Arg (RWWR; SEQ ID NO:396), Arg-Tyr-Try-Arg (RYYR; SEQ ID NO:397), Arg-Phe-Trp-Arg (RFWR; SEQ ID NO:398), Arg-Trp-Phe-Arg (RWFR; SEQ ID NO:399), Arg-Phe-Tyr-Arg (RFYR; SEQ ID NO:400), Arg-Tyr-Phe-Arg (RYFR; SEQ ID NO:401), Arg-Trp-Tyr-Arg (RWYR; SEQ ID NO:402), and Arg-Tyr-Trp-Arg (RYWR; SEQ ID NO:403). In other alternatives, sequence X in Formula VII... 1b -Y 2a -Y 2b -X 2aThe following groups can be selected: His-Phe-Phe-His (HFFH; SEQ ID NO:404), His-Trp-Trp-His (HWWH; SEQ ID NO:405), His-Tyr-Try-His (HYYH; SEQ ID NO:406), His-Phe-Trp-His (HFWH; SEQ ID NO:407), His-Trp-Phe-His (HWFH; SEQ ID NO:408), His-Phe-Tyr-His (HFYH; SEQ ID NO:409), His-Tyr-Phe-His (HYFH; SEQ ID NO:410), His-Trp-Tyr-His (HWYH; SEQ ID NO:411), and His-Tyr-Trp-His (HYWH; SEQ ID NO:412).

[0146] amino acid residue X in formula VII 1a The amino acid residue X can be selected from the following groups: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E). In other embodiments, amino acid residue X 1a The group consisting of Arg(R) and Gln(Q) is selected. In some embodiments, amino acid residue X in formula VII... 1a For Arg(R). Optionally, amino acid residue X in formula VII 1a You can choose from the following groups: Lys(K), Gln(Q), Glu(E), and Asn(N).

[0147] amino acid residue X in formula VII 2b The amino acid residue X can be selected from the following groups: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E). In other embodiments, amino acid residue X 2b The group consisting of Arg(R) and Gln(Q) is selected. In some embodiments, amino acid residue X in formula VII... 2b For Arg(R). Optionally, amino acid residue X in formula VII 2b You can choose from the following groups: Lys(K), Gln(Q), Glu(E), and Asn(N).

[0148] amino acid residue Y in formula VII 1aThe following groups can be selected: Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). In some embodiments, amino acid residue Y in Formula VII... 1a The following groups are selected: Phe (F), Trp (W), and Tyr (Y). Optionally, amino acid residues Y in Formula VII... 1a You can choose from the following groups: Leu(L), Cys(C), Met(M), Val(V), Ile(I).

[0149] amino acid residue Y in formula VII 3a The following groups can be selected: Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). In some embodiments, amino acid residue Y in Formula VII... 3a The following groups are selected: Phe (F), Trp (W), and Tyr (Y). Optionally, amino acid residues Y in Formula VII... 3a You can choose from the following groups: Leu(L), Cys(C), Met(M), Val(V), Ile(I).

[0150] Therefore, class II anti-inflammatory peptides may comprise banded regions having sequences selected from the group consisting of, substantially composed of, or composed of, said regions: FX 1a -X 1b -FF-X 2a -X 2b -F(SEQ ID NO:9), FX 1a -X 1b -FF-X 2a -X 2b -W(SEQ ID NO:10), WX 1a -X 1b -FF-X 2a -X 2b -F(SEQ ID NO:11), FX 1a -X 1b -FW-X 2a -X 2b -F(SEQ ID NO:12), FX 1a -X 1b -WF-X 2a -X2b -F(SEQ ID NO:13), F-X 1a -X 1b -WW-X 2a -X 2b -F(SEQ ID NO:14), W-X 1a -X 1b -WW-X 2a -X 2b -F(SEQ ID NO:15), F-X 1a -X 1b -WW-X 2a -X 2b -W(SEQ ID NO:16), W-X 1a -X 1b -WW-X 2a -X 2b -W(SEQ ID NO:17), F-X 1a -X 1b -FF-X 2a -X 2b -Y(SEQ ID NO:18), Y-X 1a -X 1b -FF-X 2a -X 2b -F(SEQ ID NO:19), F-X 1a -X 1b -FY-X 2a -X 2b -F(SEQ ID NO:20), F-X 1a -X 1b -YF-X 2a -X 2b -F(SEQ ID NO:21), F-X 1a -X 1b -YY-X 2a -X 2b -F(SEQ ID NO:22), Y-X 1a -X 1b -YY-X 2a -X 2b -F(SEQ ID NO:23), F-X 1a -X 1b -YY-X 2a -X 2b -Y(SEQ ID NO:24) and Y-X 1a -X 1b -YY-X 2a -X 2b-Y(SEQ ID NO:25), YX 1a -X 1b -YY-X 2a -X 2b -W(SEQ ID NO:26), WX 1a -X 1b -YY-X 2a -X 2b -Y(SEQ ID NO:27), YX 1a -X 1b -YW-X 2a -X 2b -Y(SEQ ID NO:28), YX 1a -X 1b -WY-X 2a -X 2b -Y(SEQ IDNO:29), YX 1a -X 1b -WW-X 2a -X 2b -Y(SEQ ID NO:30), WX 1a -X 1b -WW-X 2a -X 2b -Y (SEQ ID NO:31) and YX 1a -X 1b -WW-X 2a -X 2b -W(SEQ ID NO:32). The amino acid residue X in the above sequence... 1a X 1b X 2a and X 2b You can choose as discussed above.

[0151] Class II anti-inflammatory peptides may contain a band-like affinity region, substantially composed of or consisting of said region, said region further comprising amino acid residue Y directly bound to Formula VII. 1aThe first additional amino acid residue. The first additional amino acid residue may be a hydrophobic amino acid residue (e.g., a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), Leu(L), Cys(C), Met(M), Val(V), Ile(I), Thr(T), Pro(P), Ser(S), Ala(A), and Gly(G); a residue selected from the group consisting of Phe(F), Trp(W), and Tyr(Y); a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or a residue selected from the group consisting of Leu(L), Cys(C), Met(M), Val(V), and Ile(I)). Optionally, the first additional amino acid residue may be a hydrophilic amino acid residue (e.g., a residue selected from the group consisting of Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E); a residue selected from the group consisting of Arg(R), Lys(K), and His(H); a residue selected from the group consisting of Arg(R), Lys(K), His(H), and Gln(Q); or a residue selected from the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E)).

[0152] Class II anti-inflammatory peptides may contain a band-like affinity region, substantially composed of or consisting of said region, said region further comprising amino acid residue Y directly bound to Formula VII. 3aThe first additional amino acid residue. The first additional amino acid residue may be a hydrophobic amino acid residue (e.g., a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), Leu(L), Cys(C), Met(M), Val(V), Ile(I), Thr(T), Pro(P), Ser(S), Ala(A), and Gly(G); a residue selected from the group consisting of Phe(F), Trp(W), and Tyr(Y); a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or a residue selected from the group consisting of Leu(L), Cys(C), Met(M), Val(V), and Ile(I)). Optionally, the first additional amino acid residue may be a hydrophilic amino acid residue (e.g., a residue selected from the group consisting of Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E); a residue selected from the group consisting of Arg(R), Lys(K), and His(H); a residue selected from the group consisting of Arg(R), Lys(K), His(H), and Gln(Q); or a residue selected from the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E)).

[0153] Class II anti-inflammatory peptides may contain a band-like affinity region, substantially composed of or consisting of said region, said region further comprising amino acid residue Y directly bound to Formula VII. 1a The first additional amino acid residue and the amino acid residue Y directly bound to Formula VII 3aThe second additional amino acid residue. The first additional amino acid residue may be a hydrophobic amino acid residue and the second additional amino acid residue may be a hydrophilic amino acid residue. Optionally, the first additional amino acid residue may be a hydrophilic amino acid residue and the second amino acid residue may be a hydrophobic amino acid residue. In any case, the additional hydrophobic amino acid residue may be selected from the group consisting of Phe(F), Trp(W), Tyr(Y), Leu(L), Cys(C), Met(M), Val(V), Ile(I), Thr(T), Pro(P), Ser(S), Ala(A), and Gly(G); and in some embodiments, it may be selected from the group consisting of Phe(F), Trp(W), and Tyr(Y); and in other embodiments, it may be selected from the group consisting of Phe(F). The other hydrophilic amino acid residues can be selected from the group consisting of Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E); and in some embodiments, they can be residues selected from the group consisting of Arg(R), Lys(K), and His(H); or residues selected from the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E).

[0154] Class II anti-inflammatory peptides may comprise banded affinity regions, substantially composed of or consisting of said regions, said regions comprising or consisting of sequences selected from the group of sequences listed in Table 5, such as RP124, RP132, RP134, RP142, RP147, RP151, RP166-RP172, RP175, RP177, RP182, RP183, RP185, RP186, and RP42. 4. RP190, RP194, RP198, RP199-RP202, RP204, RP206, RP207, RP209, RP210, RP212-RP216, RP218, RP219, RP425, RP225, RP227, RP233-RP239, RP398, RP241-RP247, RP250-RP256, RP426, RP427, RP285 and RP387 (i.e., SEQ ID NO: 106-173 respectively). In some embodiments, the class II anti-inflammatory peptide comprises a band-like affinity region, substantially composed of or consisting of said region, said region comprising a sequence selected from the group consisting of, substantially composed of or consisting of said sequence: RP124 (SEQ ID NO:106), RP166 (SEQ ID NO:112), RP182 (SEQ ID NO:121), and RP183 (SEQ ID NO:122).

[0155] Class XII peptides

[0156] The anti-inflammatory peptide of the present invention can be a class XII peptide. A class XII anti-inflammatory peptide may comprise a banded region containing a sequence selected from the group defined by formula XLIX, substantially consisting of or consisting of said region:

[0157] Y 1a -X 1a -Y 2a -X 2a -Y 3a -X 3a (Formula XLIX).

[0158] amino acid residue Y in formula XLIX 1a Y 2a and Y 3aEach of the following groups can be selected independently: Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In some embodiments, amino acid residues Y in formula XLIX 1a Y 2a and Y 3a Each group can be independently selected from the following groups: Phe(F), Trp(W), and Tyr(Y); Phe(F), Trp(W), Tyr(Y), and Leu(L); or Phe(F), Trp(W), Tyr(Y), Leu(L), Ile(I), Cys(C), Met(M), Val(V), and Ala(A).

[0159] amino acid residue X of formula XLIX 1a X 2a and X 3a Each of the following groups can be selected independently: Arg(R), Lys(K), His(H), Gln(Q), Glu(E), Asn(N), and Asp(D). In some embodiments, amino acid residue X 1a X 2a and X 3a Each of the following groups is independently selected: Arg(R), Lys(K), and His(H). Optionally, amino acid residue X... 1a X 2a and X 3a Each of the following groups is independently selected: Arg(R), Lys(K), His(H), and Gln(Q).

[0160] Class XII anti-inflammatory peptides may contain a band-like affinity region, substantially composed of or consisting of said region, said region further comprising a first additional amino acid residue. The first additional amino acid residue may be an amino acid residue Y directly bound to formula XLIX. 1aTherefore, the first additional amino acid residue can be, for example, a residue selected from the group consisting of Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E); a residue selected from the group consisting of Arg(R), Lys(K), and His(H); a residue selected from the group consisting of Arg(R), Lys(K), His(H), and Gln(Q); or a residue selected from the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E). Optionally, the first amino acid residue can be amino acid residue X directly bound to formula XLIX. 3a The first additional amino acid residue can be, for example, a residue selected from the group consisting of Phe(F), Trp(W), and Tyr(Y); a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), Leu(L), Ile(I), Cys(C), Met(M), Val(V), and Ala(A).

[0161] Class XII anti-inflammatory peptides may comprise a banded hydrophilic / hydrophilic region, substantially composed of or consisting of said region, said region further comprising a first and a second additional amino acid residue. The first additional amino acid residue may be a hydrophilic amino acid residue as discussed above, which directly binds to amino acid residue Y of formula XLIX. 1a The second additional amino acid residue can directly bind to the first additional amino acid residue. Therefore, the second additional amino acid residue can be a hydrophobic amino acid residue, for example, a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), Leu(L), Cys(C), Met(M), Val(V), Ile(I), Thr(T), Pro(P), Ser(S), Ala(A), and Gly(G); a residue selected from the group consisting of Phe(F), Trp(W), and Tyr(Y); a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or a residue selected from the group consisting of Leu(L), Cys(C), Met(M), Val(V), and Ile(I). Optionally, the second additional amino acid residue can be an amino acid residue X that directly binds to formula XLIX. 3a The hydrophobic amino acid residues, as discussed above.

[0162] Class XII anti-inflammatory peptides may comprise a banded affinity region, substantially composed of or consisting of said region, said region further comprising a first, second, and third additional amino acid residues. The first additional amino acid residue may be an amino acid residue Y directly bound to formula XLIX. 1a The first additional amino acid residue is a hydrophilic amino acid residue, and the second additional amino acid residue can be a hydrophobic amino acid residue that directly binds to the first additional amino acid residue, as discussed above. The third additional amino acid residue can be a hydrophilic amino acid residue that directly binds to the second additional amino acid residue. Therefore, the third additional amino acid residue can be, for example, a residue selected from the group consisting of Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E); a residue selected from the group consisting of Arg(R), Lys(K), and His(H); a residue selected from the group consisting of Arg(R), Lys(K), His(H), and Gln(Q); or a residue selected from the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E). Optionally, the third amino acid residue can be an amino acid residue X that directly binds to the first additional amino acid residue of formula XLIX. 3a The third additional amino acid residue can be, for example, a residue selected from the group consisting of Phe(F), Trp(W), and Tyr(Y); a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), Leu(L), Ile(I), Cys(C), Met(M), Val(V), and Ala(A).

[0163] Class XII anti-inflammatory peptides may comprise a band of affinity-relative regions, substantially composed of or consisting of said regions, said regions further comprising four, five, six or more additional amino acid residues. The additional amino acid residues may be added in a manner that continues an alternating pattern of hydrophobic amino acid residues followed by hydrophilic amino acid residues followed by hydrophobic amino acid residues, as shown in Formula XLIX. In this manner, class XII anti-inflammatory peptides may be extended to comprise a band of affinity-relative regions having 10, 11, 12 or more amino acid residues, substantially composed of or consisting of said regions.

[0164] Class XII anti-inflammatory peptides may include banded affinity regions, substantially composed of or consisting of said regions, said regions comprising sequences selected from the group consisting of, substantially composed of or consisting of said sequences: RP393, RP391, PR392, RP390, and RP389 (i.e., SEQ ID NO: 253-257, respectively).

[0165] XIV type peptides

[0166] The anti-inflammatory peptide of the present invention may be a class XIV peptide. A class XIV anti-inflammatory peptide may comprise a banded region containing a sequence selected from any one of the defined formulas LI to LIV, substantially consisting of or consisting of said region:

[0167] X 1a -X 1b -Y 1a -Y 1b -X 2a- Y 2a -Y 2b -Y 2c -Y 2d (Form LI)

[0168] Y 1a -Y 1b -Y 1c -Y 1d -X 1a -Y 2a -Y 2b -X 2a -X 2b (Formula LII);

[0169] Y 1a -Y 1b -X 1a -Y 2a -Y 2b -Y 2c -X 2b -Y 3a -X 3a -Y 4a (Formula LIII); and

[0170] Y 1a -X 1a -Y 2a -X 2a -Y 3a -Y 3b -Y 3c -X 3a -Y 4a -Y 4b (Formula LIV).

[0171] The banded affinity region of class XIV polypeptides may contain at least three (e.g., three to six) proline amino acid residues. For example, amino acid residue Y in formula LI 1a Y 2a and Y 2b It can be a proline amino acid residue. Optionally, the amino acid residue Y in formula LII 1c Y 1d and Y 2b It can be a proline amino acid residue. In other alternatives, amino acid residue Y in formula LIII... 1a Y 2a Y 2b Y 2c Y 3a and Y 4a It could be a proline amino acid residue. Still in other alternatives, the amino acid residue Y in formula LIV... 1a Y 2b Y 3a Y 3b Y 3c and Y 4b It can be a proline amino acid residue.

[0172] Hydrophobic amino acid residues not indicated as proline residues in formulas LI to LIV (e.g., Y) 1a Y 1b Y 1c Y 1d Y 2a Y 2b Y 2c Y 2d Y 3a Y 3b Y 3c Y 4a and Y 4b Each of these hydrophobic amino acid residues can be individually selected from the following groups: Phe(F), Trp(W), Tyr(Y), Leu(L), Cys(C), Met(M), Val(V), Ile(I), Thr(T), Pro(P), Ser(S), Ala(A), and Gly(G). In some embodiments, these hydrophobic amino acid residues are individually selected from: the group consisting of Phe(F), Trp(W), and Tyr(Y); the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or the group consisting of Leu(L), Cys(C), Met(M), Val(V), and Ile(I).

[0173] Hydrophilic amino acid residues (e.g., X) in formulas LI to LIV1a X 1b X 2a X 2b and X 3a Each of these hydrophilic amino acid residues can be individually selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E). In some embodiments, each of these hydrophilic amino acid residues is individually selected from the group consisting of: Arg(R), Lys(K), His(H), and Gln(Q); or the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E).

[0174] Class XIV anti-inflammatory peptides may include banded affinity regions, substantially composed of or consisting of said regions, said regions comprising sequences selected from the group consisting of, substantially composed of or consisting of said sequences: RP449, RP450, RP448, RP447, RP452, RP451, RP444, RP441, RP446, RP445, RP442, and RP443 (i.e., SEQ ID NO: 258-269, respectively).

[0175] Other categories of peptides

[0176] The anti-inflammatory peptides of the present invention can be any of classes II to XI and XIII. Such anti-inflammatory peptides may comprise banded regions of a sequence containing a group of sequences selected from any one of formulas IV to XLVIII and L, substantially consisting of or consisting of said regions.

[0177] Hydrophobic amino acid residues (e.g., Y) in formulas IV to XLVIII and L 1a Y 1b Y 1c Y 1d Y 1e Y 2a Y 2b Y 2c Y 2d Y 2e Y 3a Y 3b Y 3c Y 4a and Y 4bEach of these hydrophobic amino acid residues can be individually selected from the following groups: Phe(F), Trp(W), Tyr(Y), Leu(L), Cys(C), Met(M), Val(V), Ile(I), Thr(T), Pro(P), Ser(S), Ala(A), and Gly(G). In some embodiments, these hydrophobic amino acid residues are individually selected from: the group consisting of Phe(F), Trp(W), and Tyr(Y); the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or the group consisting of Leu(L), Cys(C), Met(M), Val(V), and Ile(I).

[0178] Hydrophilic amino acid residues (e.g., XLVIII and L) in formulas IV to XLVIII and L 1a X 1b X 1c X 1d X 2a X 2b X 2c X 2d X 3a X 3b X 3c X 4a and X 4b Each of these hydrophilic amino acid residues can be individually selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E). In some embodiments, each of these hydrophilic amino acid residues is individually selected from the group consisting of: Arg(R), Lys(K), His(H), and Gln(Q); or the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E).

[0179] The anti-inflammatory peptide of any one of formulas IV to XLVIII and L may comprise a banded affinity region, substantially composed of or consisting of said region, said region further comprising a first amino acid residue directly bound to the formula (e.g., Y). 1a or X 1a(or) can be added to the first additional amino acid residue of the last amino acid residue in the formula. The first additional amino acid residue can be a hydrophilic amino acid residue (e.g., a residue selected from the group consisting of Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E); a residue selected from the group consisting of Arg(R), Lys(K), and His(H); a residue selected from the group consisting of Arg(R), Lys(K), His(H), and Gln(Q); or a residue selected from the group consisting of Asn(N), Gln(Q), Asp(D), and Glu(E)). Optionally, the first additional amino acid residue may be a hydrophobic amino acid residue (e.g., a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), Leu(L), Cys(C), Met(M), Val(V), Ile(I), Thr(T), Pro(P), Ser(S), Ala(A), and Gly(G); a residue selected from the group consisting of Phe(F), Trp(W), and Tyr(Y); a residue selected from the group consisting of Phe(F), Trp(W), Tyr(Y), and Leu(L); or a residue selected from the group consisting of Leu(L), Cys(C), Met(M), Val(V), and Ile(I)).

[0180] The anti-inflammatory peptide of any one of formulas IV to XLVIII and L may comprise a banded affinity region, substantially composed of or consisting of said region, said region further comprising a first and a second additional amino acid residue, wherein the first additional amino acid residue is directly bound to the first amino acid residue of the formula (e.g., Y). 1a or X 1a The first amino acid residue can be either the first amino acid residue, the last amino acid residue, or the first additional amino acid residue in the formula, and the second additional amino acid residue can be directly bound to the first amino acid residue, the last amino acid residue, or the first additional amino acid residue in the formula. The first additional amino acid residue can be a hydrophilic or hydrophobic amino acid residue as discussed above. The second additional amino acid residue can also be a hydrophilic or hydrophobic amino acid residue as discussed above.

[0181] The anti-inflammatory peptide of any one of Formulas IV to XLVIII and Formula L may comprise a band-like affinity region, substantially composed of or consisting of said region, said region comprising a sequence selected from the group consisting of, substantially composed of or consisting of said sequence: RP396, RP405, RP174, RP176, RP178, RP180-181, RP184, RP408, RP187, RP416, RP188, RP189, RP388, RP417, RP191-RP193, RP4 04, RP196, RP397, RP197, RP402, RP203, RP409, RP205, RP208, RP217, RP220-RP224, RP226, RP229, RP231, RP240, RP248, RP249, RP415, RP257, RP259-RP266, RP269, RP272, RP274, RP277-RP279, RP282, RP283, RP286, RP289 and RP414 (i.e., SEQ ID NO: 174-233 respectively).

[0182] Variant peptides

[0183] The exemplary anti-inflammatory peptide sequences shown in Tables 3-9 (hereinafter) are merely examples and not limited to the anti-inflammatory peptides presented herein. In fact, fragments and variants of the disclosed peptide sequences are within the scope of this invention.

[0184] The “fragments” of this invention comprise at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive amino acid residues (or up to one fewer amino acid residue than the subject polypeptide) of the polypeptide disclosed herein and retain at least one anti-inflammatory property of the subject polypeptide. Therefore, fragments of this invention include polypeptides that have one, two, three, four, or more amino acids missing from their N-terminus and / or C-terminus relative to the polypeptides disclosed herein.

[0185] The “variants” of this invention are polypeptides that are substantially similar to the polypeptides disclosed herein and retain at least one anti-inflammatory property of the subject polypeptide. Variants may comprise the deletion (i.e., truncation) of one or more amino acid residues at the N-terminus or C-terminus of the subject polypeptide disclosed herein; the deletion and / or addition of one or more amino acid residues at one or more internal sites of the subject polypeptide disclosed herein; and / or the substitution of one or more amino acid residues at one or more positions of the subject polypeptide disclosed herein. For subject polypeptides of 12 amino acids or less in length, the variant polypeptide may comprise three or fewer (e.g., two, one, or none) amino acid residues deleted at the N-terminus and / or C-terminus, whether or not they are located internally.

[0186] Therefore, the present invention further provides an anti-inflammatory polypeptide that is at least 50% identical (e.g., at least 60%, 70%, 80%, 90% or greater) to any of the anti-inflammatory polypeptides disclosed in Tables 3-9 and still retains at least one anti-inflammatory property. For example, the present invention provides an anti-inflammatory polypeptide having a length of 3 to 24 amino acid residues and comprising a banded affinity region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90% or greater identity) with a class I anti-inflammatory polypeptide (e.g., any of the sequences in Table 3), substantially composed of or composed of said region. Such identity may be shared, for example, with RP-394 (SEQ ID NO:33), RP-108 (SEQ ID NO:34), RP-113 (SEQ ID NO:39), RP-118 (SEQ ID NO:44), RP-129 (SEQ ID NO:54), or RP-179 (SEQ ID NO:86). Optionally, the present invention provides an anti-inflammatory polypeptide of 3 to 24 amino acid residues in length and comprising a banded affinity region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90% or greater identity) with class II (subclass 1) anti-inflammatory polypeptides (e.g., any of the sequences in Table 5), substantially composed of or composed of said region. Such identity may be shared, for example, with RP-124 (SEQ ID NO: 106), RP-134 (SEQ ID NO: 108), RP-166 (SEQ ID NO: 112), RP-168 (SEQ ID NO: 114), RP-182 (SEQ ID NO: 121), or RP-183 (SEQ ID NO: 122). In other alternatives, the present invention provides an anti-inflammatory polypeptide of 3 to 24 amino acid residues in length and comprising a banded affinity region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or greater) with any class II to IX or XIII anti-inflammatory polypeptide (e.g., any sequence in Table 6), and substantially composed of or composed of said region. In other alternatives, the present invention provides an anti-inflammatory polypeptide of 3 to 24 amino acid residues in length and comprising a banded affinity region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or greater) with any class VIII to XI anti-inflammatory polypeptide (e.g., any sequence in Table 7), and substantially composed of or composed of said region.In other alternatives, the present invention provides an anti-inflammatory polypeptide of 3 to 24 amino acid residues in length and comprising a banded region of at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or greater) with any combination of sequences in Table 8, and substantially composed of or consisting of said region. In other alternatives, the present invention provides an anti-inflammatory polypeptide of 3 to 24 amino acid residues in length and comprising a banded region of at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or greater) with any combination of sequences in Table 9, and substantially composed of or consisting of said region.

[0187] Differences between homologous anti-inflammatory peptides and any of the anti-inflammatory peptides in Tables 3-9 in terms of band affinity regions can include the deletion, addition, and / or substitution of amino acid residues, as discussed above. Substituted amino acid residues may be unrelated to the replaced amino acid residues (e.g., unrelated in terms of hydrophobicity / hydrophilicity, size, charge, polarity, etc.), or the substituted amino acid residues may constitute similar, conserved, or highly conserved amino acid substitutions. As used herein, “similar,” “conserved,” and “highly conserved” amino acid substitutions are defined as shown in Table 2 below. The determination of whether an amino acid residue substitution is similar, conserved, or highly conserved is based exclusively on the side chain of the amino acid residue, rather than the peptide backbone, which may be modified to increase peptide stability, as discussed below.

[0188] Table 2: Classification of amino acid substitutions

[0189]

[0190] In some embodiments, the variant peptides of the present invention bind to two or more targets (e.g., pro-inflammatory targets). In some embodiments, the variant peptides bind to three, four, five, or more pro-inflammatory targets. For example, the variant peptides may bind to any combination of targets disclosed herein (e.g., NF-κB class II proteins and human serum albumin (HSA)), as discussed below. Such binding may be based on computer data, in vitro data, or in vivo data.

[0191] Modeling of peptides that bind to target molecules

[0192] The determination of whether a peptide possesses anti-inflammatory properties can be performed on a computer. For example, the binding of a peptide (e.g., a peptide having a length of 3 to 24 amino acid residues and containing a banded affinity region constituting at least 25% of the peptide length) to a putative target molecule can be modeled on a computer using any of the many molecular modeling and docking platforms available in the art, thereby assessing whether the peptide is an anti-inflammatory peptide. (ClusPro online) TM Algorithm version 2.0 (developed by Boston University) is particularly well-suited for modeling the conformation of peptides and their binding to target molecules, such as signaling proteins, as described in the examples listed below. Modeling algorithms that allow peptide docking with target molecules, such as ClusPro, can be used. TM Algorithms, such as those used to predict binding energies associated with peptide-target interactions, provide reasonable assessments of these energies; however, they are not necessarily equal to binding energies calculated from in vitro assays of peptide and protein targets. Therefore, all binding energies identified in this paper were determined using ClusPro. TM The algorithm generates the value. Therefore, in the absence of a contrary indication, any numerical reference for the binding energy associated with the binding of a peptide and a specific target is obtained by using ClusPro. TM The algorithm uses the binding energy as a reference for modeling interactions.

[0193] As detailed in the following examples, exemplary RP peptides have been shown to interact with various inflammation-associated signaling molecules, including NF-κB class II subunits RelB, TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, as well as other membrane-associated signaling molecules, including CD206, CD47, and SIRP-α, translationally modified protein transglutaminase 2 (TGM2), and histone-modifying enzyme histone methyltransferase (HMT). Amphiphilic clefts are often generated as these protein targets fold into their normal three-dimensional conformation, exhibiting high affinity for the immunomodulatory peptides described herein.

[0194] For modeling the interaction between a potential anti-inflammatory peptide and an NF-κB class II subunit, any class II subunit sequence (e.g., RelA, ReIB, cRel, NF-κB1, or NF-κB2) can be used. In some embodiments, the class II subunit sequence folds into a functional class II subunit or a functional fragment thereof. The specific class II subunit used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human NF-κB class II subunit if the expected subject is human, bovine NF-κB class II subunit if the expected subject is bovine, etc.). The NF-κB class II subunit used for modeling can be a human ReIB sequence (NCBI accession number NP-006500), as follows:

[0195] MLRSGPASGPSVPTGRAMPSRRVARPPAAPELGALGSPDLSSLSLAVSRSIDELEIIDEYIKENGFGLDGGQPGPGEGLPRLVSRGAASLSTVTLGPVAPPATPPPWGCPLGRLVSPAPGPGPQPHLVTTEQPKQRGMRFRYR CEGRSAGSILGRSSTEASKTLPAIELRDCGGLREVEVTACLVWKDWPHRVHPHSLVGKDCTDGICRVRLRPHVSPRHSFNNLGIQCVRKKEIEAAIERKIQLGIDPYNAGSLKNHQEVDMNVVRICFQASYRDQQGQMRRMDPV LSEPVYDKK STNTSELRICRINKESGPCTGGEELYLLCDKVQKEDISVVFSRASWEGRADFSQADVHRQIAIVFKTPPYEDLEIV EPVTVNVFLQRLTDGVCSEPLPFTYLPR DHDSYGVDKKRKRGMPDVLGELNSSDPHGIESKRRKKKPAILDHFLPNHGSGPFLPPSALLPDPDFFSGTVSLPGLEPPGGPDLLDDGFAYDPTAPTLFTMLDLLPPAPPHASAVVCSGGAGAVVGETPGPEPLTLDSYQAPGPGDGGTASLVGSNMFPNHYREAAFGGGLLSPGPEAT (SEQ ID NO: 367).

[0196] The underlined sequence in human RelB (above) has been identified as a dimerizing domain. The highlighted amino acid residues (Tyr-300, Leu-302, and His-332) are believed to be particularly important in the dimerizing interactions.

[0197] Anti-inflammatory peptides can be identified based on their ability to bind (e.g., on a computer) to dimerization pockets of class II subunits and / or to interfere with or block the dimerization of class II subunits. For example, anti-inflammatory peptides can bind to at least one amino acid residue of human RelB (SEQ ID NO: 367) selected from the group consisting of: Leu-281, Ile-283, Cys-284, Glu-298, Tyr-300, Leu-301, Leu-302, Cys-303, Ile-311, Ser-312, Ala-329, Asp-330, Val-331, His-332, Gln-334, and Leu-371, or equivalent amino acid residues in different human NF-κB class II proteins or NF-κB class II proteins of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human RelB (SEQ ID NO: 367) selected from the group consisting of Glu-298, Tyr-300, Leu-302, Asp-330, Gln-334 and LeH-371, or an equivalent amino acid residue in different human NF-κB class II proteins or NF-κB class II proteins of another species.

[0198] In some embodiments, the anti-inflammatory peptide binds to human RelB (SEQ ID NO: 367) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050, -1075, -1100, -1125, -1150, -1200 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example, using ClusPro. TM Binding affinity detected by the algorithm.

[0199] For modeling the interaction between potential anti-inflammatory peptides and TGFβ, any TGFβ protein sequence can be used. TGFβ sequences are typically folded into a functional TGFβ protein or a functional fragment thereof. The TGFβ protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human TGFβ if the intended subject is human, bovine TGFβ if the intended subject is bovine, etc.). The sequence used for modeling can be a human TGFβ sequence (NCBI accession number NP_000651.3), as follows:

[0200] MPPSGLRLLPLLLPLLWLLVLTPGRPAAGLSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGPLPEAVLALYNSTRDRVAGESAEPEPEPEADYYAKEVTRVLMVETHNEIYDKFKQSTHSIYMFFNTSELREAVPEPVLLSRAELRLLRLKLKVEQHVELYQKYSNNSWRYLSNRLLAPSDSPEWLS FDVTGVVRQWLSRGGEIEGFRLSAHCSCDSRDNTLQVDINGFTTGRRGDLATIHGMNRPFLLLMATPLERAQHLQSSRHRRALDTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS(SEQ ID NO: 368).

[0201] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to a receptor binding site on TGFβ and / or to interfere with or block the binding of TGFβ to its receptor. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of human TGFβ (SEQ ID NO: 368) selected from the group consisting of: Arg-25, Gly-29, Trp-30, Lys-31, Trp-32, Ile-33, His-34, Tyr-91, Val-92, Val-93, Gly-94, Arg-95, Lys-96, and Pro-97, or equivalent amino acid residues in a TGFβ protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human TGFβ (SEQ ID NO: 368) selected from the group consisting of: Leu-20, Ile-22, Phe-24, Asp-27, Leu-28, Trp-30, Trp-32, Tyr-39, Phe-43, Pro-80, Leu-83, Leu-101, and Ser-112, or an equivalent amino acid residue of a TGFβ protein from another species. Alternatively, the anti-inflammatory peptide may bind to at least one amino acid residue of human TGFβ (SEQ ID NO: 368) selected from the group consisting of: Asp-27, Leu-28, Trp-30, and Trp-32, or an equivalent amino acid residue of a TGFβ protein from another species.

[0202] In some embodiments, the anti-inflammatory peptide may bind to human TGFβ (SEQ ID NO: 368) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0203] For modeling the interaction between potential anti-inflammatory peptides and Notch1, any Notch1 protein sequence can be used. The Notch1 sequence used for modeling is typically folded into the functional Notch1 protein or its calcium-binding fragment. The Notch1 protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human Notch1 if the intended subject is human, bovine Notch1 if the intended subject is bovine, etc.). The sequence used for modeling can be the human Notch1 sequence (GenBank accession number AAG33848.1), as follows:

[0204]

[0205] Anti-inflammatory peptides can be identified based on their ability to bind to a calcium-binding site on Notch1 and / or to interfere with or block Notch1's ability to bind to calcium. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of human Notch1 (SEQ ID NO: 369) selected from the group consisting of: Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala-1553, Glu-1556, Trp-1557, Cys-1562, His-1602, Arg-1684, Gln-1685, Cys-1686, Ser-1691, Cys-1693, Phe-1694, and Phe-1703, or equivalent amino acid residues in Notch1 protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human Notch1 (SEQ ID NO: 369) selected from the group consisting of Phe-1520, Trp-1557, Cys-1562 and Phe-1703, or an equivalent amino acid residue of Notch1 protein of another species.

[0206] In some embodiments, the peptide of the present invention binds to human Notch1 (SEQ ID NO: 369) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050, -1075 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example, using ClusPro. TM Binding affinity detected by the algorithm.

[0207] For modeling the interaction between potential anti-inflammatory peptides and Wnt8R, any Wnt8R protein sequence can be used. The Wnt8R sequence used for modeling is typically folded into a functional Wnt8R protein or its Wnt8-binding fragment. The Wnt8R protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human Wnt8R if the intended subject is human, bovine Wnt8R if the intended subject is bovine, etc.). The sequence used for modeling can be, for example, a bovine Wnt8R sequence (NCBI accession number XP_005214377.1), as follows:

[0208] MEWGYLLLEVTSLLAALALLQRSSGAAASAKELACQEITVPLCKGIGYNYTYMPNQFNHDTQDEAGLEVHQFWPLVEIQCSPDLKFFLCSMYTPICLEDYKKPLPPCRSVCERAKAGCAPLMRQYGFAWPDRMRCDRLPEQGNPDTLCMDYNRTDLTTAASSVDGDPVAGICYVGNQSLDNLLGFVLAPLVIYLFIG TMFLLAGFVSLFRIRSVIKQQGGPTKTHKLEKLMIRLGLFTVLYTVPAAVVVACLFYEQHNRPRWEATHNCPCLRDLQPDQARRPDYAVFMLKYFMCLVVGITSGVWVWSGKTLESWRALCTRCWASKGAGAAGAGAAGGGPGGPGAGGGGGPGAGGAGSLYSDVSTGLTWRSGTASSVSYPKQMPLSQV(SEQ ID NO: 370).

[0209] Anti-inflammatory peptides can be identified based on their ability to bind to a Wnt ligand binding site on Wnt8R and / or to interfere with or block the binding of Wnt8R to a Wnt ligand (e.g., Wnt8). For example, an anti-inflammatory peptide can bind to at least one amino acid residue of bovine Wnt8R (SEQ ID NO: 370) selected from the group consisting of Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr-100, Lys-101, Pro-103, Pro-105, Pro-106, Arg-137, and Asp-145, or an equivalent amino acid residue of a Wnt8R protein from another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of bovine Wnt8R (SEQ ID NO: 370) selected from the group consisting of Tyr-52, Phe-57, Tyr-100 and Asp-145, or an equivalent amino acid residue of Wnt8R protein of another species.

[0210] In some embodiments, the polypeptide of the present invention can bind to bovine Wnt8R (SEQ ID NO: 370), wherein the affinity is at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -875, -900, -925, -950, -975 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0211] For modeling the interaction between potential anti-inflammatory peptides and TRAIL, any TRAIL protein sequence can be used. In some embodiments, the TRAIL sequence used for modeling folds into a functional TRAIL protein or a functional fragment thereof. The TRAIL protein sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human TRAIL is selected if the expected subject is human, bovine TRAIL is selected if the expected subject is bovine, etc.). The sequence used for modeling can be a human TRAIL sequence (GenBank accession number EAW78466.1), as follows:

[0212] KEKQQNISPLVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKINSWESSRSGHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKNDKQMVQYIYKYTSYPDPILLMKSARNSCWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDHEASFFGAFLVG (SEQ ID NO: 371).

[0213] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to a receptor binding site on TRAIL and / or to interfere with or block TRAIL's ability to bind to its receptor. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of human TRAIL (SEQ ID NO: 371) selected from the group consisting of: Arg-130, Arg-158, Ser-159, Gly-160, His-161, Phe-163, Tyr-189, Arg-189, Gln-193, Glu-195, Glu-236, Tyr-237, Leu-239, Asp-267, Asp-269, His-270, and Glu-271, or equivalent amino acid residues in the TRAIL protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human TRAIL (SEQ ID NO: 371) selected from the group consisting of: Ala-123, His-161, Ser-162, Phe-163, Tyr-183, Tyr-185, Tyr-243, His-270, Glu-271, Phe-274, Phe-278, Leu-279, and Val-280, or an equivalent amino acid residue in a TRAIL protein of another species. Alternatively, the anti-inflammatory peptide may bind to at least one amino acid residue of human TRAIL (SEQ ID NO: 371) selected from the group consisting of: Phe-163, Tyr-243, Glu-271, and Phe-278, or an equivalent amino acid residue in a TRAIL protein of another species.

[0214] In some embodiments, the anti-inflammatory peptide may bind to human TRA1L (SEQ ID NO: 371) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0215] For modeling the interaction between potential anti-inflammatory peptides and IL6R, any IL6R protein sequence can be used. The IL6R sequence used for modeling is typically folded into a functional IL6R protein or its IL6-binding fragment. The IL6R protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human IL6R if the intended subject is human, bovine IL6R if the intended subject is bovine, etc.). The sequence used for modeling can be a human IL6R sequence (NCBI accession number NP_786943.1), as follows:

[0216] MLTLQTWLVQALFIFLTTESTGELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWAT HKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDNIASF(SEQ ID NO: 372).

[0217] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an IL6-binding site on IL6R and / or to interfere with or block the binding of IL6R to its ligand IL6. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of human IL6R (SEQ ID NO: 372) selected from the group consisting of Glu-163, Gly-164, Phe-168, Gln-190, Phe-229, Tyr-230, Phe-279, and Gln-281, or an equivalent amino acid residue in an IL6R protein of another species. Alternatively, an anti-inflammatory peptide may bind to at least one amino acid residue of human IL6R (SEQ ID NO: 372) selected from the group consisting of Leu-108, Glu-140, Pro-162, Phe-229, Tyr-230, and Phe-279, or an equivalent amino acid residue in an IL6R protein of another species. In other alternatives, the anti-inflammatory peptide may bind to at least one amino acid residue of human IL6R (SEQ ID NO: 372) selected from the group consisting of: Glu-140, Phe-229, Tyr-230, Phe-279, or an equivalent amino acid residue in the IL6R protein of another species.

[0218] In some embodiments, the anti-inflammatory peptide may bind to human IL6R (SEQ ID NO: 372) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example, using ClusPro. TM Binding affinity detected by the algorithm.

[0219] For modeling the interaction between potential anti-inflammatory peptides and IL10R, any suitable IL10R protein sequence can be used. The IL10R sequence used for modeling is typically folded into a functional IL10R protein or its IL10-binding fragment. The IL10R protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human IL10R if the intended subject is human, bovine IL10R if the intended subject is bovine, etc.). The sequence used for modeling can be a human IL10R sequence (NCBI accession number NP_001549.2), as follows:

[0220] MLPCLVVLLAALLSLRLGSDAHGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGEFCVQVKPSVASRSNKGMWSKEECISLTRQYFTVTNVIIFFAFVLLLSGALAYCLALQLYVRRRKKLPSVLLFKKPSPFIFISQRPSPETQDTIHPLDEEAFLKVSPELKNLDLHGSTDSGFGSTKPSLQTEEPQFLLPDPHPQADRTLGNREPPVLGDSCSSGSSNSTDSGICLQEPSLSPSTGPTWEQQVGSNSRGQDDSGIDLVQNSEGRAGDTQGGSALGHHSPPEPEVPGEEDPAAVAFQGYLRQTRCAEEKATKTGCLEEESPLTDGLGPKFGRCLVDEAGLHPPALAKGYLKQDPLEMTLASSGAPTGQWNQPTEEWSLLALSSCSDLGISDWSFAHDLAPLGCVAAPGGLLGSFNSDLVTLPLISSLQSSE(SEQ ID NO:373)。

[0221] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an IL10 binding site on IL10R and / or to interfere with or block the binding of IL10R to its ligand IL10. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of human IL10R (SEQ ID NO: 373) selected from the group consisting of Tyr-43, Ile-45, Glu-46, Asp-61, Asn-73, Arg-76, Asn-94, Arg-96, Phe-143, Ala-189, Ser-190, and Ser-191, or an equivalent amino acid residue of IL6R protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human IL10R (SEQ ID NO: 373) selected from the group consisting of Leu-41, Arg-42, Tyr-43, Ile-45, Glu-46, Ser-47, Trp-48, Arg-76, and Arg-78, or an equivalent amino acid residue in an IL10R protein of another species. Alternatively, the anti-inflammatory peptide may bind to at least one amino acid residue of human IL10R (SEQ ID NO: 373) selected from the group consisting of Tyr-43, Ile-45, Glu-46, and Trp-48, or an equivalent amino acid residue in an IL10R protein of another species.

[0222] In some embodiments, the anti-inflammatory peptide may bind to human IL10R (SEQ ID NO: 373) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -775, -800, -825, -850, -875, -900 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0223] For modeling the interaction between potential anti-inflammatory peptides and EGFR, any EGFR protein sequence can be used. The EGFR sequence used for modeling is typically folded into a functional EGFR protein or its ligand-binding fragment. The EGFR protein sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human EGFR if the expected subject is human, bovine EGFR if the expected subject is bovine, etc.). Alternatively, the sequence used for modeling can be a Drosophila EGFR sequence (GenBank accession number AAR85273.1), as follows:

[0224] KICIGTKSRLSVPSNKEHHYRNLRDRYTNCTYVDGNLELTWLPNENLDLSFLDNIREVTGYILISHVDVKKVVFPKLQIIRGRTLFSLSVEEEKYALFVTYSKMYTLEIPDLRDVLNGQVGFHNNYNLCHMRTIQWSEIVSNGTDAYYNYDFTAPERECPKCHESCTHGCWGEGPKNCQKFSKLTCSPQCAGGRCYGPKPRECCHLFCAGGCTGPTQKDCIACKNFFDEGVCKEECPPMRKYNPTTYVLETNPEGKYAYGATCVKECPGHLLRDNGACVRSCPQDKMDKGGECVPCNGPCPKTCPGVTVLHAGNIDSFRNCTVIDGNIRILDQTFSGFQDVYANYTMGPRYIPLDPERLEVFSTVKEITGYLNIEGTHPQFRNLSYFRNLETIHGRQLMESMFAALAIVKSSLYSLEMRNLKQISSGSVVIQHNRDLCYVSNIRWPAIQKEPEQKVWVNENLRADLCEKNGTICSDQCNEDGCWGAGTDQCLNCKNFNFNGTCIADCGYISNAYKFDNRTCKICHPECRTCNGAGADHCQECVHVRDGQHCVSECPKNKYNDRGVCRECHATCDGCTGPKDTIGIGACTTCNLAIINNDATVKRCLLKDDKCPDGYFWEYVHPQEQGSLKPLAGRAVCRKCHPLCELCTNYGYHEQ(SEQ ID NO:374)。

[0225] Anti-inflammatory peptides can be identified, for example, based on their ligand-binding sites on EGFR and / or their ability to interfere with or block the binding of at least one ligand to EGFR. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of Drosophila EGFR (SEQ ID NO: 374) selected from the group consisting of Leu-10, Thr-40, Trp-41, Asp-48, Phe-51, Leu-63, His-66, Asp-68, Leu-88, and Tyr-101, or an equivalent amino acid residue in an EGFR protein of another species. Alternatively, an anti-inflammatory peptide may bind to at least one amino acid residue of Drosophila EGFR (SEQ ID NO: 374) selected from the group consisting of Trp-41, Asp-48, Phe-51, Asp-68, and Tyr-101, or an equivalent amino acid residue in an EGFR protein of another species.

[0226] In some embodiments, the anti-inflammatory peptide can bind to Drosophila EGFR (SEQ ID NO: 374) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity can correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0227] For modeling the interaction between potential anti-inflammatory peptides and CDK6, any CDK6 protein sequence can be used. The CDK6 sequence used for modeling is typically folded into a functional CDK6 protein or a functional fragment thereof. The CDK6 protein sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human CDK6 if the expected subject is human, bovine CDK6 if the expected subject is bovine, etc.). The sequence used for modeling can be a human CDK6 sequence (NCBI accession number NP_001250.1), as follows:

[0228] MEKDGLCRADQQYECVAEIGEGAYGKVFKARDLKNGGRFVALKRVRVQTGEEGMPLSTIREVAVLRHLETFEHPNVVRLFDVCTVSRTDRETKLTLVFEHVDQDLTTYLDKVPEPGVPTETIKDMMFQLLRGLDFLHSHRVVHRDLKPQNILVTSSGQIKLADFG LARIYSFQMALTSVVVTLWYRAPEVLLQSSYATPVDLWSVGCIFAEMFRRKPLFRGSSDVDQLGKILDVIGLPGEEDWPRDVALPRQAFHSKSAQPIEKFVTDIDELGKDLLLKCLTFNPAKRISAYSALSHPYFQDLERCKENLDSHLPPSQNTSELNTA(SEQ ID NO: 375).

[0229] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on CDK6 and / or to interfere with or block the kinase activity of CDK6 or the ability of CDK6 to phosphorylate one or more CDK6 substrates. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of human CDK6 (SEQ ID NO: 375) selected from the group consisting of: Val-142, Arg-144, Asp-145, Ser-171, Val-180, Val-181, Leu-183, Arg-186, Val-190, Gln-193, Tyr-196, and Val-200, or equivalent amino acid residues in a CDK6 protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human CDK6 (SEQ ID NO: 375) selected from the group consisting of Asp-145, Val-180 and Tyr-196, or an equivalent amino acid residue in the CDK6 protein of another species.

[0230] In some embodiments, the anti-inflammatory peptide may bind to human CDK6 (SEQ ID NO: 375) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0231] For modeling the interaction between potential anti-inflammatory peptides and histone methyltransferases (HMTs), any HMT protein sequence can be used. The HMT sequence used for modeling is typically folded into a functional HMT protein or a functional fragment thereof. The HMT protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human HMT if the intended subject is human, bovine HMT if the intended subject is bovine, etc.). A sequence used for modeling could be, for example, the Paramecium bursaria Chlorella virus 1 HMT sequence (NCBI accession number NP_048968.1), as follows:

[0232] MFNDRVIVKKSPLGGYGVFARKSFEKGELVEECLCIVRHNDDWGTALEDYLFSRKNMSAMALGFGAIFNHSKDPNARHELTAGLKRMRIFTIKPIAIGEEITISYGDDYWLSRPRLTQN (SEQ ID NO: 376).

[0233] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on HMT and / or to interfere with or block the methyltransferase activity of HMT or the ability of HMT to methylate histone substrates. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of *Paramecium glomeratum* HMT (SEQ ID NO: 376) selected from the group consisting of Asn-69, His-70, Ser-71, Lys-72, Asp-73, Pro-74, and Asn-75, or an equivalent amino acid residue in the HMT protein of another species. Alternatively, an anti-inflammatory peptide may bind to at least one amino acid residue of *Paramecium glomeratum* HMT (SEQ ID NO: 376) selected from the group consisting of Tyr-16, Glu-48, Tyr-50, Leu-51, Phe-52, and Asn-69, or an equivalent amino acid residue in the HMT protein of another species.

[0234] In some embodiments, the anti-inflammatory peptide may bind to *Paramecium spp.* HMT (SEQ ID NO: 376) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0235] For modeling the interaction between potential anti-inflammatory peptides and the CD47 protein, any CD47 protein sequence can be used. The CD47 sequence used for modeling is typically folded into the functional CD47 protein or its SIRP-α-binding portion. The CD47 protein sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human CD47 if the expected subject is human, bovine CD47 if the expected subject is bovine, etc.). The sequence used for modeling can be a human CD47 sequence (NCBI accession number XP_005247966.1), as follows:

[0236] MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELTREGETIIELKYRVVSWFSPNENILIVIFP IFAILLFWGQFGIKTLKYRSGGMDEKTIALLVAGLVITVIVIVGAILFVPGEYSLKNATGGLIVTSTGILILLHYYVFSTAIGLTSFVIAILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVE(SEQID NO: 377).

[0237] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to the SIRP-α-binding site on the HMT and / or to interfere with or block the binding of CD47 to SIRP-α. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of CD47 (SEQ ID NO: 377) selected from the group consisting of: Glu-29, Ala-30, Glu-35, Val-36, Tyr-37, Lys-39, Thr-49, Asp-51, Glu-97, Thr-99, Leu-101, Thr-102, Arg-103, Glu-104, and Glu-106, or equivalent amino acid residues in the CD47 protein of another species. In some embodiments, the anti-inflammatory peptide may bind to at least one amino acid residue of CD47 (SEQ ID NO: 377) selected from the group consisting of: Glu-29, Glu-35, Lys-39, Glu-97, Leu-101, Thr-102, Arg-103, Glu-104, and Glu-106, or an equivalent amino acid residue in the CD47 protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human CD47 (SEQ ID NO: 377) selected from the group consisting of: Tyr-16, Glu-48, Tyr-50, Leu-51, Phe-52 and Asn-6Tyr-37, Thr-49, Phe-50, Asp-51, Ala-53, Glu-97, Val-98, Glu-100, Leu-101, Thr-102, Glu-104, Glu-106, Gly-107, or equivalent amino acid residues in the CD47 protein of another species. In some embodiments, the anti-inflammatory peptide may bind to at least one amino acid residue of CD47 (SEQ ID NO: 377) selected from the group consisting of Tyr-37, Glu-97, Glu-100, Leu-101, Glu-104, Glu-106, or an equivalent amino acid residue in the CD47 protein of another species.

[0238] In some embodiments, the anti-inflammatory peptide may bind to human CD47 (SEQ ID NO: 377) with an affinity of at least -550 kcal / mol, and in some embodiments at least -600, -650, -675, -700, -725, -750, -775, -800 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0239] For modeling the interaction between potential anti-inflammatory peptides and SIRP-α, any SIRP-α protein sequence can be used. The SIRP-α sequence used for modeling is typically folded into a functional SIRP-α protein or its CD47-binding fragment. The SIRP-α protein sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human SIRP-α if the expected subject is human, bovine SIRP-α if the expected subject is bovine, etc.). The sequence used for modeling can be a human SIRP-α sequence (GenBank accession number AAH26692.1), as follows:

[0240] MEPAGPAPGRLGPLLCLLLAASCAWSGVAGEEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKG SPDTEFKSGAGTELSVRAKPSAPVVSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHSTAKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTL EVTQQPVRAENQVNVTCQVRKFYPQRLQLTWLENGNVSRTETASTVTENKDGTYNWMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVSAHPKEQGSNTAAENTGSNERNIYIVVGVVCTLLV ALLMAALYLVRIRQKKAQGSTSSTRLHEPEKNAREITQVQSLDTNDITYADLNLPKGKKPAPQAAEPNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK(SEQ ID NO: 378).

[0241] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to the HMT-binding site on SIRP-α and / or to interfere with or block the binding of SIRP-α to HMT. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of SIRP-α (SEQ ID NO: 378) selected from the group consisting of Leu-30, Gln-37, Gln-52, Lys-53, Ser-66, Thr-67, Arg-69, Met-72, Phe-74, Lys-96, and Asp-100, or equivalent amino acid residues in the SIRP-α protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human SIRP-α (SEQ ID NO: 378) selected from the group consisting of Tyr-50, Gln-52, Pro-58, Ser-66, Thr-67, and Ser-77, or an equivalent amino acid residue in a SIRP-α protein of another species. In some embodiments, the anti-inflammatory peptide may bind to at least one amino acid residue of SIRP-α (SEQ ID NO: 378) selected from the group consisting of Tyr-50, Gln-52, Ser-66, and Thr-67, or an equivalent amino acid residue in a SIRP-α protein of another species.

[0242] In some embodiments, the anti-inflammatory peptide may bind to human SIRP-α (SEQ ID NO: 378) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -825, -850, -875, -900, -925, -950, -975, -1000 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example, using ClusPro. TM Binding affinity detected by the algorithm.

[0243] For modeling the interaction between potential anti-inflammatory peptides and CD206, any CD206 protein sequence can be used. The CD206 sequence used for modeling is typically folded into a functional CD206 protein or its mannose-binding fragment. The CD206 protein sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human CD206 if the expected subject is human, bovine CD206 if the expected subject is bovine, etc.). The sequence used for modeling can be a human CD206 sequence (NCBI accession number NP_002429.1), as follows:

[0244]

[0245] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to the mannose-binding site on CD206 and / or to interfere with or block the binding of SIRP-mannose to CD206. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of CD206 (SEQ ID NO: 379) selected from the group consisting of Glu-725, Tyr-729, Glu-733, Asn-747, and Asp-748, or an equivalent amino acid residue in the CD206 protein of another species. Optionally, an anti-inflammatory peptide may bind to at least one amino acid residue of human CD206 (SEQ ID NO: 379) selected from the group consisting of Phe-708, Thr-709, Trp-710, and Pro-714. Glu-719, Asn-720, Trp-721, Ala-722, Glu-725, Tyr-729, Glu-733, Asn-747, Asp-748, Ser-1691, Cys-1693, Phe-1694, and Phe-1703, or equivalent amino acid residues in the CD206 protein of another species. In some embodiments, the anti-inflammatory peptide may bind to at least one amino acid residue of CD206 (SEQ ID NO: 379) selected from the group consisting of: Phe-708, Trp-710, Trp-721, Glu-725, Tyr-729, Glu-733, or equivalent amino acid residues in the CD206 protein of another species.

[0246] In some embodiments, the anti-inflammatory peptide may bind to human CD206 (SEQ ID NO: 379) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0247] For modeling the interaction between potential anti-inflammatory peptides and TGM2, any TGM2 protein sequence can be used. The TGM2 sequence used for modeling is typically folded into a functional TGM2 protein or its acyltransferase catalytic fragment. The TGM2 protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human TGM2 if the intended subject is human, bovine TGM2 if the intended subject is bovine, etc.). The sequence used for modeling can be a human TGM2 sequence (GenBank accession number AAB95430.1), as follows:

[0248] (SEQ ID NO: 380).

[0249] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on TGM2 and / or interfere with or block the acyltransferase activity of TGM2. For example, anti-inflammatory peptides can bind to at least one amino acid residue of TGM2 selected from the group consisting of (SEQ ID NO: 380): Cys-277, His-335, and Asp-358, or equivalent amino acid residues in the TGM2 protein of another species.

[0250] In some embodiments, the anti-inflammatory peptide may bind to human TGM2 (SEQ ID NO: 380) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0251] For modeling the interaction between potential anti-inflammatory peptides and serum albumin, any serum albumin sequence can be used. The serum albumin sequence used for modeling is typically folded into a functional serum albumin or a functional fragment thereof. The serum albumin sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human serum albumin (HSA) if the expected subject is human, bovine serum albumin (BSA) if the expected subject is bovine, etc.). The sequence used for modeling can be a human serum albumin (HSA) sequence (NCBI accession number NP_000468.1), as follows:

[0252] (SEQ ID NO: 381).

[0253] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to HSA under physiological conditions (e.g., in the bloodstream).

[0254] In some embodiments, the anti-inflammatory peptide may bind to HSA (SEQ ID NO: 381) with an affinity of at least -650 kcal / mol, and in some embodiments at least -700, -750, -800, -850, -900, -925, -950, -975, -1000, -1025, -1050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0255] In some embodiments, the anti-inflammatory peptide binds to two or more targets (e.g., pro-inflammatory targets). In some embodiments, the anti-inflammatory peptide binds to three, four, five, or more pro-inflammatory targets. For example, the anti-inflammatory peptide may bind to any combination of targets disclosed herein. Such binding may be based on computer data, in vitro data, or in vivo data. Thus, the anti-inflammatory peptide may bind to two or more NF-κB class II subunits (e.g., RelB and at least one other NF-κB class II subunit, such as RelA, cRel, NF-κB1, or NF-κB2). Optionally (or additionally), the anti-inflammatory peptide may bind to an NF-κB class II subunit (e.g., RelB) and at least one other signaling molecule (e.g., at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, CDK6, CD206, CD47, SIRP-α, HMT, and TGM2). For example, an anti-inflammatory peptide may bind to an NF-κB class II subunit (e.g., Re1B) and at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6. Alternatively, the anti-inflammatory peptide may bind to an NF-κB class II subunit (e.g., Re1B) and at least one signaling molecule selected from the group consisting of CD206, CD47, SIRP-α, and TGM2. In other alternatives, the anti-inflammatory peptide may bind to an NF-κB class II subunit (e.g., Re1B) and HMT. In other alternatives, the anti-inflammatory peptide may bind to at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, and at least one signaling molecule selected from the group consisting of CD206, CD47, SIRP-α, and TGM2. In other alternatives, the anti-inflammatory peptide may bind to at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, and also to HMT. Still in other embodiments, the anti-inflammatory peptide may bind to at least one NF-κB class II subunit (e.g., RelB), at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, at least one signaling molecule selected from the group consisting of CD206, CD47, SIRP-α, and TGM2, and also to HMT. In some embodiments, the anti-inflammatory peptide binds to two or more pro-inflammatory targets and also to serum albumin (e.g., human serum albumin).

[0256] For modeling the interaction between potential anti-inflammatory peptides and LEGUMAIN, any LEGUMAIN protein sequence can be used. The LEGUMAIN sequence used for modeling is typically folded into a functional LEGUMAIN protein or a functional fragment thereof. The LEGUMAIN protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human LEGUMAIN if the intended subject is human, bovine LEGUMAIN if the intended subject is bovine, etc.). The sequence used for modeling can be a human LEGUMAIN sequence (GenBank accession number AAH03061.1).

[0257] MVWKVAVFLSVALGIGAIPIDDPEDGGKHWVVIVAGSNGWYNYRHQADACHAYQIIHRNGIPDEQIVVMMYDDIAYSEDNPTPGIVINRPNGTDVYQGVPKDYTGEDVT PQNFLAVLRGDAEAVKGIGSGKVLKSGPQDHVFIYFTDHGSTGILVFPNEDLHVKDLNETIHYMYKHKMYRKMVFYIEACESGSMMNHLPDNINVYATTAANPRESSYA CYYDEKRSTYLGDWYSVNWMEDSDVEDLTKETLHKQYHLVKSHTNTSHVMQYGNKTISTMKVMQFQGMKRKASSPVPLPPVTHLDLTPSPDVPLTIMKRKLMNTNDLEE SRQLTEEIQRHLDARHLIEKSVRKIVSLLAASEAEVEQLLSERAPLTGHSCYPEALLHFRTHCFNWHSPTYEYALRHLYVLVNLCEKPYPLHRIKLSMDHVCLGHY(SEQ ID NO: 413).

[0258] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on LEGUMAIN and / or to interfere with or block LEGUMAIN's binding to its target. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of human LEGUMAIN (SEQ ID NO: 413) selected from the group consisting of Asn-44, Arg-46, His-159, Glu-189, Cys-191, Ser-217, Ser-218, and Asp-233, or an equivalent amino acid residue in a LEGUMAIN protein of another species. Alternatively, an anti-inflammatory peptide may bind to at least one amino acid residue of human LEGUMAIN (SEQ ID NO: 413) selected from the group consisting of Asn-44, Glu-189, and Asp-233, or an equivalent amino acid residue in a LEGUMAIN protein of another species.

[0259] In some embodiments, the anti-inflammatory peptide may bind to human LEGUMAIN (SEQ ID NO: 413) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0260] For modeling the interaction between potential anti-inflammatory peptides and CD209, any CD209 protein sequence can be used. The CD209 sequence used for modeling is typically folded into a functional CD209 protein or a functional fragment thereof. The CD209 protein sequence used for modeling can be selected based on the type of subject to be treated by the anti-inflammatory peptide (e.g., human CD209 if the expected subject is human, bovine CD209 if the expected subject is bovine, etc.). The sequence used for modeling can be a human CD209 sequence (GenBank accession number NP_001138366.1).

[0261] MSDSKEPRLQQLGLLVSKVPSSISQEQSRQDAIYQNLTQLKAAVGELSEKSKLQEIYQELTQLKAAVGELPEKSKLQEIYQELTRLKAAVG ELPEKSKLQEIYQELTWLKAAVGELPEKSKMQEIYQELTRLKAAVGELPEKSKQQEIYQELTRLKAAVGELPEKSKQQEIYQELTRLKAAV GELPEKSKQQEIYQELTQLKAAVERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSRDEEQFLSPAPATPNPPPA(SEQ ID NO:414)

[0262] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on CD209 and / or to interfere with or block the binding of CD209 to its receptor. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of human CD209 (SEQ ID NO: 414) selected from the group consisting of: Phe-269, Glu-280, Glu-303, Asn-305, Asn-306, Glu-310, Asp-311, Ser-316, Gly-317, Asn-321, and Lys-324, or an equivalent amino acid residue of CD209 protein from another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human CD209 (SEQ ID NO: 414) selected from the group consisting of: Phe-269, Glu-280, Glu-303, Glu-310, Asp-311, Asn-321 and Lys-324, or an equivalent amino acid residue of CD209 protein of another species.

[0263] In some embodiments, the anti-inflammatory peptide may bind to human CD209 (SEQ ID NO: 414) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950, -1,000, -1,050 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro.TM Binding affinity detected by the algorithm.

[0264] For modeling the interaction between potential anti-inflammatory peptides and FAS, any FAS protein sequence can be used. The FAS sequence used for modeling is typically folded into a functional FAS protein or a functional fragment thereof. The FAS protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human FAS if the intended subject is human, bovine FAS if the intended subject is bovine, etc.). The sequence used for modeling can be a human FAS sequence (NCBI reference sequence: NP_000034.1).

[0265] MLGIWTTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEG SRSNLGWLCLLLLPIPLIVWVKRKEVQKTCRKHRKENQGSHESPTLNPETVAINLSDVDLSKYITTIAGVMTLSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTIILKDITSDSENSNFRNEIQSLV(SEQ ID NO: 415).

[0266] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on FAS and / or to interfere with or block the binding of FAS to its ligands. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of human FAS (SEQ ID NO: 415) selected from the group consisting of Lys-251, Lys-296, Lys-299, Leu-303, Leu-306, Ala-307, Glu-308, Lys-309, Gln-311, Ile-314, Leu-315, Asp-317, Ile-318, and Thr-319, or equivalent amino acid residues in FAS proteins of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human FAS (SEQ ID NO: 415) selected from the group consisting of Lys-296, Lys-299, Leu-306, Ala-307, Glu-308, Ile-314, Leu-315, Asp-317, and Ile-318, or an equivalent amino acid residue of FAS protein from another species.

[0267] In some embodiments, the anti-inflammatory peptide may bind to human FAS (SEQ ID NO: 415) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0268] Programmed cell death protein 1, also known as PD-1 and CD279 (differentiation cluster 279), is a protein encoded by the PDCD1 gene in humans. PD-1 is a cell surface receptor belonging to the immunoglobulin superfamily and is expressed on T cells and B-cells. PD-1 binds to two ligands, PD-L1 and PD-L2. PD-1 acts as an immune checkpoint, playing a crucial role in downregulating the immune system by preventing T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is achieved through a dual mechanism: promoting apoptosis (programmed cell death) in antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressive T cells).

[0269] For modeling the interaction between potential anti-inflammatory peptides and PD-1, any PD-1 protein sequence can be used. The PD-1 sequence used for modeling is typically folded into a functional PD-1 protein or a functional fragment thereof. The PD-1 protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human PD-1 if the intended subject is human, bovine PD-1 if the intended subject is bovine, etc.). The sequence used for modeling can be a human PD-1 sequence (locus: XP_006712636.1).

[0270] MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLP NGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARG(SEQ ID NO: 416).

[0271] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on PD-1 and / or to interfere with or block the binding of PD-1 to its receptor. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of human PD-1 (SEQ ID NO: 416) selected from the group consisting of Val-64, Asn-66, Tyr-68, Met-70, Thr-76, Lys-78, Thr-120, Leu-122, Ala-125, Ser-127, or an equivalent amino acid residue in the PD-1 protein of another species. Alternatively, an anti-inflammatory peptide may bind to at least one amino acid residue of human PD-1 (SEQ ID NO: 416) selected from the group consisting of Tyr-68, Met-70, Lys-78, and Leu-122, or an equivalent amino acid residue in the PD-1 protein of another species.

[0272] In some embodiments, the anti-inflammatory peptide may bind to human PD-1 (SEQ ID NO: 416) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950, -1,000 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro.TM Binding affinity detected by the algorithm.

[0273] Bispecific mitogen-activated protein kinase 7 (MKK7), also known as MAP kinase 7 or MKK7, is an enzyme encoded by the MAP2K7 gene in humans. This protein is a member of the mitogen-activated protein kinase kinase family. MKK7 exists as six distinct isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (I and II isoforms). MKK7 is involved in signal transduction mediating cellular responses to pro-inflammatory cytokines and environmental stress. This kinase specifically activates MAPK8 / JNK1 and MAPK9 / JNK2, and the kinase itself is phosphorylated and activated by MAP kinase kinases, including MAP3K1 / MEKK1, MAP3K2 / MEKK2, MAP3K3 / MEKK5, and MAP4K2 / GCK.

[0274] For modeling the interaction between potential anti-inflammatory peptides and MKK7, any MKK7 protein sequence can be used. The MKK7 sequence used for modeling is typically folded into a functional MKK7 protein or a functional fragment thereof. The MKK7 protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., human MKK7 if the intended subject is human, bovine MKK7 if the intended subject is bovine, etc.). The sequence used for modeling can be a human MKK7 sequence (NCBI reference sequence: NP_001284484.1).

[0275] MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPIIVITLSPAPAPSQRAALQLPLANDGGSRSPSSESSPQHPTPPARPRHMLGLPSTLFTPRSMESIEID QKLQEIMKQTGYLTIGGQRYQAEINDLENLGEMGSGTCGQVWKMRFRKTGHVIAVKQMRRSGNKEENKRILMDLDVVLKSHDCPYIVQCFGTFITNTDVFIAMELMGTCA EKLKKRMQGPIPERILGKMTVAIVKALYYLKEKHGVIHRDVKPSNILLDERGQIKLCDFGISGRLVDSKAKTRSAGCAAYMAPERIDPPDPTKPDYDIRADVWSLGISLV ELATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDCLTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR(SEQ ID NO: 417).

[0276] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on MKK7 and / or to interfere with or block the binding of MKK7 to its receptor. For example, an anti-inflammatory peptide can bind to at least one amino acid residue of human MKK7 (SEQ ID NO: 417) selected from the group consisting of: Met-142, Val-150, Lys-152, Lys-165, Met-212, Met-215, Thr-217, Lys-221, Leu-266, Cys-276, and Asp-277, or equivalent amino acid residues in MKK7 protein of another species. Optionally, the anti-inflammatory peptide may bind to at least one amino acid residue of human MKK7 (SEQ ID NO: 417) selected from the group consisting of: Met-142, Val-150, Lys-165, Met-212, Met-215, Leu-266, and Asp-277, or an equivalent amino acid residue of MKK7 protein of another species.

[0277] In some embodiments, the anti-inflammatory peptide may bind to human MKK7 (SEQ ID NO: 417) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950, -1,000 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0278] For modeling the interaction between potential anti-inflammatory peptides and ribonucleotide reductases (RNRs), any RNR protein sequence can be used. The RNR sequence used for modeling is typically folded into a functional RNR protein or a functional fragment thereof. The RNR protein sequence used for modeling can be selected based on the type of subject the anti-inflammatory peptide is intended to treat (e.g., a human RNR if the intended subject is human, a bovine RNR if the intended subject is bovine, etc.). The sequence used for modeling can be a human RNR sequence (GenBank: AJV34160.1).

[0279] (SEQ ID NO: 418).

[0280] Anti-inflammatory peptides can be identified, for example, based on their ability to bind to an active site on an RNR and / or to interfere with or block the binding of an RNR to its receptor. For example, an anti-inflammatory peptide may bind to at least one amino acid residue of human RNR (SEQ ID NO: 418) selected from the group consisting of Asn-426, Leu-427, Cys-428, Glu-430, Met-606, Pro-608, and Ala-610, or an equivalent amino acid residue in an RNR protein of another species.

[0281] In some embodiments, the anti-inflammatory peptide may bind to human RNR (SEQ ID NO: 418) with an affinity of at least -600 kcal / mol, and in some embodiments at least -650, -700, -750, -800, -850, -900, -925, -950, -1,000 kcal / mol or greater. The required binding affinity may correspond to a binding affinity that can be detected in vitro or in vivo. Optionally, the required binding affinity may correspond to a binding affinity that can be detected on a computer, for example using ClusPro. TM Binding affinity detected by the algorithm.

[0282] Excluded peptides

[0283] The compositions of the present invention optionally exclude polypeptides that satisfy the structural algorithms described herein and known in the art prior to the filing of this application. Various publications have discussed synthetic and naturally occurring anti-inflammatory polypeptides and / or polypeptides having banded affinity sequences, including, for example, U.S. Patent Applications Nos. 2012 / 0270770 and 2003 / 0109452 and U.S. Patent No. 6,559,281. Therefore, one or more polypeptides and / or uses of such polypeptides described in such publications may be excluded from the scope of the compositions and / or methods currently disclosed. For example, peptide RP-398 (SEQ ID NO: 155) may optionally be excluded from the compositions described herein and / or methods using such compositions. Additionally, any polypeptide disclosed in Tables 3-9 below may optionally be excluded from the compositions disclosed herein and / or methods using such compounds.

[0284] Linked anti-inflammatory peptide combinations

[0285] This invention further includes any two anti-inflammatory peptides already linked together. The linking can be formed by a peptide linker connecting the C-terminus of a first anti-inflammatory peptide to the N-terminus of a second anti-inflammatory peptide, such as a Gly-Gly-Gly (GGG), Gly-Gly-Gly-Arg (GGGR), Gly-Pro-Gly (GPG), or Gly-Pro-Gly-Arg (GPGR) sequence. Optionally, the linking can be a peptide linker (e.g., a poly-N-substituted form of any of the above peptide linkers), a polymer containing a g-amino acid (e.g., corresponding to any of the above peptide linkers), or a non-peptide chemical linker. The linked anti-inflammatory peptides can be any of the peptides disclosed herein (e.g., in Tables 3-9), and can include the same peptide linked to form a homodimer or different peptides linked to form a heterodimer. Techniques for linking multiple peptides via peptide linkers and non-peptide linkers are well known in the art, and inventive peptide combinations are expected to include all such links.

[0286] Anti-inflammatory peptides can be linked to another molecule via degradable bonds such as disulfide bonds. Disulfide bonds can be mediated by the thiol groups of cysteine ​​residues visible in the anti-inflammatory peptide and thiol groups in other molecules. The cysteine ​​residues can, for example, be located at the C-terminus or N-terminus of the anti-inflammatory peptide. Specific examples include RP-433 (FAKKFAKKFKC, SEQ ID NO:384) and RP-434 (KFRKAFKRFFC; SEQ ID NO:385), although any peptide disclosed herein can be similarly modified. Using this type of disulfide linking, the peptides of the present invention can be conveniently linked to a wide variety of useful molecules. For example, the linking can be using another anti-inflammatory peptide (which optionally contains C-terminal or N-terminal cysteine ​​residues), a fluorescent tag (e.g., Dylight 350), a chemotherapeutic agent (e.g., a paclitaxel derivative formed by adding a thiol group to an appropriate site on the paclitaxel ring structure, followed by oxidation of the cysteine-containing peptide of the present invention), etc.

[0287] The linked anti-inflammatory peptide (e.g., a homodimer or heterodimer) can bind to a target molecule (e.g., a target protein, such as a pro-inflammatory signaling protein) with a binding energy greater than that of the individual monomeric peptide. Thus, for example, the binding energy of the linked anti-inflammatory peptide to an NF-κB class II protein (e.g., RelB) can be at least -700 kcal / mol, and in some embodiments is at least -750, -800, -900, -1000, -1100, -1200, -1250, -1300, -1350, -1400, -1425, -1450, -1475, -1500, -1525, -1550, -1575, -1600 kcal / mol or greater. The binding energy can be determined, for example, on a computer, in vitro, or in vivo using methods well known in the art (e.g., using ClusPro). TM Algorithms are used to determine this.

[0288] Modified peptides

[0289] Embodiments of the present invention include modifications of any of the anti-inflammatory peptides of the present invention by chemical or genetic means. Examples of such modifications include peptide structures having partial or complete sequences of non-natural amino acids and / or natural amino acids in L or D form. For example, any peptide disclosed herein and any variant thereof can be generated entirely in D form. Additionally, the peptides of the present invention can be modified to contain a carbohydrate or lipid moiety, such as a sugar or fatty acid, covalently linked to an N-terminal or C-terminal side chain of an amino acid. Furthermore, the peptides of the present invention can be modified to enhance solubility and / or half-life upon administration. For example, polyethylene glycol (PEG) and related polymers have been used to enhance the solubility and half-life of protein therapeutics in blood. Therefore, the peptides of the present invention can be modified by PEG polymers, etc. The peptides of the present invention can also be modified to contain sulfur, phosphorus, halogens, metals, etc. And amino acid mimics can be used to generate the peptides of the present invention (e.g., having a structure-based algorithm structure or a structure similar to any of the anti-inflammatory peptides disclosed herein). In some embodiments, the peptides of the present invention containing amino acid mimics have enhanced properties, such as resistance to degradation. For example, the polypeptides of the present invention may comprise one or more (e.g., all) peptide monomers.

[0290] Composition

[0291] The compositions of the present invention comprise an anti-inflammatory polypeptide that satisfies the structural algorithm described herein. For example, the anti-inflammatory polypeptide has banded affinity regions having sequences corresponding to any one of Formulas I-LIV. Specifically, the anti-inflammatory polypeptide can be any polypeptide or fragment or variant thereof listed in Tables 3-9. Typically, the anti-inflammatory polypeptide included in the compositions of the present invention will be a synthetic polypeptide (e.g., prepared by chemical synthesis and / or recombinant generation).

[0292] The compositions of the present invention may comprise a single anti-inflammatory polypeptide or a combination thereof. The compositions may be substantially free of proteins and other polypeptides that do not satisfy the structural algorithm disclosed herein. As used herein, the term "substantially free of proteins and other polypeptides" means that less than 5% of the protein content of the composition consists of proteins and other polypeptides that are not anti-inflammatory polypeptides of the present invention. Compositions substantially free of the non-anti-inflammatory polypeptides of the present invention may have less than 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or less of proteins or other polypeptides that do not satisfy the structural algorithm disclosed herein. Therefore, the compositions may be substantially free of blood proteins, such as serum albumin, globulins, fibrinogen, and coagulation factors. Optionally, the compositions may be substantially free of globulins, fibrinogen, and coagulation factors, but may contain purified or recombinant serum albumin.

[0293] In some embodiments, the compositions of the present invention contain anti-inflammatory peptides that are not naturally present in humans or other mammals or animals. However, the compositions of the present invention may contain anti-inflammatory peptides naturally present in humans or other mammals or animals, provided that the compositions are substantially free of biomolecules associated with or co-purified with the anti-inflammatory peptides in vivo (such as non-anti-inflammatory peptides, nucleic acids, lipids, carbohydrates, and metabolites). As used herein, the term "substantially free of biomolecules" means that less than 5% of the dry weight of the composition consists of biomolecules that are not anti-inflammatory peptides. A composition substantially free of such biomolecules may have less than 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or less of non-anti-inflammatory peptide biomolecules. Thus, for example, the compositions may be substantially free of biomolecules abundant in blood, such as proteins, fatty acids, cholesterol, non-protein clotting factors, metabolites, etc., discussed above. Additionally, the compositions may be substantially free of cells, including red blood cells, white blood cells, platelets, and cell debris.

[0294] The compositions of the present invention may contain at least 1 mg (e.g., at least 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000 mg or more) of an anti-inflammatory polypeptide. Therefore, for example, the composition may contain an anti-inflammatory peptide in an amount equal to about 1 mg to about 1000 mg (e.g., about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 1 ... About 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 75 mg to about 500 mg, about 75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about 250 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 75 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or any other range containing two or more endpoints).

[0295] The compositions of the present invention may comprise a solution containing at least 1 mg / ml (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg / ml or more) of an anti-inflammatory peptide. Therefore, for example, the composition may comprise a solution having a concentration of about 1 mg / ml to about 1000 mg / ml (e.g., about 5 mg / ml to about 900 mg / ml, about 5 mg / ml to about 800 mg / ml, about 5 mg / ml to about 700 mg / ml, about 5 mg / ml to about 600 mg / ml, about 5 mg / ml to about 500 mg / ml, about 10 mg / ml to about 500 mg / ml, about 10 mg / ml to about 400 mg / ml, about 10 mg / ml to about 10 mg / ml). g / ml to about 300 mg / ml, about 10 mg / ml to about 250 mg / ml, about 10 mg / ml to about 200 mg / ml, about 10 mg / ml to about 150 mg / ml, about 10 mg / ml to about 100 mg / ml, about 50 mg / ml to about 500 mg / ml, about 50 mg / ml to about 400 mg / ml, about 50 mg / ml to about 300 mg / ml, about 50 mg / ml to about 250 mg / ml, about 50 mg / ml to about 200 mg / ml, about 50 mg / ml to about 150 mg / ml, about 50 mg / ml to about 100 mg / ml, about 75 mg / ml to about 500 mg / ml, about 75 mg / ml to about 400 mg / ml, about 75 mg / ml to about 300 mg / ml, about 75 mg / ml to about 250 mg / ml, about 75 mg / ml to about 200 mg / ml, about 75 mg / ml to about 150 mg / ml, about Solutions of anti-inflammatory peptide concentrations of 75 mg / ml to about 100 mg / ml, about 100 mg / ml to about 500 mg / ml, about 100 mg / ml to about 400 mg / ml, about 100 mg / ml to about 300 mg / ml, about 100 mg / ml to about 250 mg / ml, about 100 mg / ml to about 200 mg / ml, about 10 mg / ml to about 150 mg / ml, or any other range containing two or more endpoints.

[0296] The compositions of the present invention comprise pharmaceutical compositions. Such pharmaceutical compositions may comprise one or more anti-inflammatory peptides and a pharmaceutically acceptable carrier. The pharmaceutical compositions may further comprise proteins and / or chemotherapeutic agents in addition to the anti-inflammatory peptides of the present invention. Other proteins may be therapeutic agents, such as therapeutic antibodies. The therapeutic proteins or antibodies may have anti-inflammatory properties or be enhanced by or enhance other properties of the anti-inflammatory peptides of the present invention. Optionally, other proteins may be carrier proteins, such as serum albumin (e.g., HSA). Serum albumin (e.g., HAS, BSA, etc.) may be purified or recombinant. By mixing the anti-inflammatory peptides in the pharmaceutical composition with serum albumin, the anti-inflammatory peptides can be effectively “loaded” onto serum albumin, thereby allowing a larger quantity of the anti-inflammatory peptides to be successfully delivered to the site of inflammation. Chemotherapy agents may be, for example, anticancer chemotherapeutic agents. These chemotherapy agents include, but are not limited to, gemcitabine, docetaxel, bleomycin, erlotinib, gefitinib, lapatinib, imatinib, dasatinib, nilotinib, besutinib, crizotinib, ceritinib, trametinib, bevacizumab, sunitinib, sorafenib, trastuzumab, ado-trastuzumab emtansine, rituximab, ipilimumab, rapamycin, tesirolimus, everolimus, methotrexate, doxorubicin, abraxane, folfirinox, cisplatin, carboplatin, 5-fluorouracil, teysumo, paclitaxel, dehydrocortisone, levothyroxine, and pemetrexed.

[0297] method

[0298] The anti-inflammatory peptides of this invention provide a powerful tool for reducing inflammation and / or treating symptoms (whether acute or chronic) associated with excessive inflammation. As used herein, the terms "treat" and similar words are intended to mean stabilizing a medical condition, reducing the symptoms of said medical condition, preventing the occurrence of said medical condition, or curing said medical condition.

[0299] Therefore, the present invention provides a method for reducing the expression level and / or activity of at least one (e.g., 2, 3, 4, 5 or more) pro-inflammatory cytokines at a site of inflammation in a subject. The method comprises administering to the subject an anti-inflammatory peptide of the present invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory peptide). The pro-inflammatory cytokines may be selected from the group consisting of NF-κB, TNFα, IL-1, IL-6, IL-8, IL-12, IL-17, IL-23, MCP-1, MMP-1, and MMP-9. The reduction may be a reduction in the expression or activity of the cytokine of at least 10% (e.g., 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or greater).

[0300] The present invention also provides a method for inhibiting an increase in the expression level and / or activity of at least one (e.g., 2, 3, 4, 5 or more) pro-inflammatory cytokines at potential sites of inflammation in a subject. The method comprises administering to the subject an anti-inflammatory peptide of the present invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory peptide). The pro-inflammatory cytokines may be selected from the group consisting of NF-κB, TNFα, IL-1, IL-6, IL-8, IL-12, IL-17, IL-23, MCP-1, MMP-1, and MMP-9. The method can inhibit this increased cytokine expression and / or activity by limiting the increase to no more than 20% (e.g., 15%, 12.5%, 10%, 7.5%, 5%, 4%, 3%, 2%, 1% or less).

[0301] This invention also provides a method for treating or preventing symptoms associated with chronic inflammation. Symptoms associated with chronic inflammation may include irritable bowel disease, ulcerative colitis, colitis, Crohn's disease, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, immune diseases, feline or human immunodeficiency virus (FIV or HIV) infection, cancer, age-related inflammation and / or stem cell dysfunction (e.g., age-related increase in Nlrp3 expression, age-related SOCS3 elevation in muscle stem cells, etc.), graft-versus-host disease (GVHD), keloids, scleroderma, obesity, diabetes, diabetic trauma, other chronic trauma, atherosclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, macular degeneration, gout, gastric ulcer, gastritis, mucositis, toxoplasmosis, and chronic viral or microbial diseases (e.g., chronic bacterial or protozoan infections). The method includes administering the anti-inflammatory peptide of the present invention (or, for example, a pharmaceutical composition containing an anti-inflammatory peptide) to a subject suffering from or likely to develop the condition.

[0302] The present invention also provides methods for treating or preventing fibrosis. Fibrosis can be, for example, pulmonary fibrosis, skin fibrosis, liver fibrosis, kidney fibrosis, or fibrosis caused by ionizing radiation. The methods include administering the anti-inflammatory peptide of the present invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory peptide) to a subject suffering from or likely to develop fibrosis.

[0303] This invention also provides a method for treating cancer. The cancer may be colon cancer, breast cancer, leukemia, lymphoma, ovarian cancer, prostate cancer, liver cancer, lung cancer, testicular cancer, cervical cancer, bladder cancer, endometrial cancer, kidney cancer, melanoma, thyroid cancer, or brain cancer or eye cancer. The method includes administering the anti-inflammatory peptide of this invention (or, for example, a pharmaceutical composition containing an anti-inflammatory peptide) to a subject suffering from cancer.

[0304] For any one or more methods, the subject may be an animal, such as a domesticated animal (e.g., a horse, cow, pig, goat, sheep, rabbit, chicken, turkey, duck, etc.), a pet (e.g., a dog, cat, rabbit, hamster, gerbil, bird, fish, etc.), a laboratory animal (e.g., a mouse, rat, monkey, chimpanzee, owl, fish, etc.), a zoo animal (e.g., a gorilla, orangutan, chimpanzee, monkey, elephant, camel, zebra, wild boar, lion, tiger, giraffe, bear, bird, etc.), a wild animal (e.g., a deer, wolf, cougar, bird, etc.), or a human.

[0305] In combination with any of the above methods, anti-inflammatory peptides can be administered at specific doses and frequencies, depending on the animal type, size, and the condition to be treated. Typically, anti-inflammatory peptides are administered in doses between about 1 mg and about 1000 mg (e.g., about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg). The dosage (approximately 50 mg to approximately 150 mg, approximately 50 mg to approximately 100 mg, approximately 75 mg to approximately 500 mg, approximately 75 mg to approximately 400 mg, approximately 75 mg to approximately 300 mg, approximately 75 mg to approximately 250 mg, approximately 75 mg to approximately 200 mg, approximately 75 mg to approximately 150 mg, approximately 75 mg to approximately 100 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 250 mg, approximately 100 mg to approximately 200 mg, or any other range containing two or more endpoints) may be administered once daily (once every other day or once weekly). The daily dose may be administered once daily or divided into smaller doses taken at multiple times throughout the day. For humans (and other mammals of similar size), a dose of 5 mg / kg may be administered every other day. Anti-inflammatory peptides can be administered at fixed intervals (e.g., 2-3 weeks), or until the levels of pro-inflammatory cytokines have decreased or stabilized, chronic inflammatory symptoms or fibrosis have lessened, or cancer has been relieved.

[0306] The administration of anti-inflammatory peptides (or pharmaceutical compositions containing such peptides) in combination with any of one or more methods may be performed intravenously, intraperitoneally, parenterally, in situ, subcutaneously, locally, nasally, orally, sublingually, intraocularly, via an implantable reservoir, using a nanoparticle-based delivery system, microneedle patch, microsphere, bead, osmotic pump or mechanical pump and / or other mechanical device.

[0307] In combination with any of the methods described above, anti-inflammatory peptides (or pharmaceutical compositions containing such peptides) may be administered in combination with another drug designed to reduce or prevent inflammation, treat or prevent chronic inflammation or fibrosis, or treat cancer. In each case, the anti-inflammatory peptide may be administered before, simultaneously with, or after the administration of the other drug. For the treatment of cancer, anti-inflammatory peptides may be administered in combination with chemotherapeutic agents selected from the group consisting of: steroids, anthracyclines, thyroid hormone replacement drugs, thymidine acid-targeting drugs, chimeric antigen receptor / T-cell therapies, and other cell therapies. Specific chemotherapeutic agents include, for example, gemcitabine, docetaxel, bleomycin, erlotinib, gefitinib, lapatinib, imatinib, dasatinib, nilotinib, besutinib, crizotinib, ceritinib, trametinib, bevacizumab, sunitinib, sorafenib, trastuzumab, ado-trastuzumab emtansine, rituximab, ipilimumab, rapamycin, tanciolimus, everolimus, methotrexate, doxorubicin, abraxane, folfirinox, cisplatin, carboplatin, 5-fluorouracil, Teysumo, paclitaxel, dehydrocortisone, levothyroxine, and pemetrexed.

[0308] Alternatively, for the treatment of cancer, anti-inflammatory peptides (or pharmaceutical compositions containing such peptides) can be administered in combination with radiation therapy. Furthermore, the anti-inflammatory peptides can be administered before or after radiation therapy.

[0309] Any of the methods described above in this invention further includes the step of evaluating the efficacy of the therapeutic treatment. Because the anti-inflammatory peptides of this invention have a demonstrably proven ability to reduce tissue inflammation and inhibit the production of inflammatory mediators such as IL-1, IL-6, IL-12, and TNFα in tissues and serum (data not shown), the efficacy of the therapeutic treatment can be assessed by measuring the levels of such cytokines (e.g., in serum) to determine whether said levels have appropriately responded to the treatment. Depending on the cytokine levels, the dosage of the anti-inflammatory peptides can be adjusted up or down as needed.

[0310] Example

[0311] Example 1: Peptide Design

[0312] Designing peptides on a computer to contain alternating X m Module and Y n The striped affinity regions of the module, where each X m The module has one to five hydrophilic amino acid residues and each Y n The module has one to five hydrophobic residues.

[0313] The initial design focused on polypeptides composed of banded affinity regions with a total length of approximately 10 amino acid residues, where each X m The module has one or two hydrophilic amino acid residues and each Y n The module has one or two hydrophobic residues, and the ratio of hydrophobic amino acid residues to hydrophilic amino acid residues is approximately 1:1. Such polypeptides are predicted to have an amphiphilic helical secondary structure, with a hydrophobic surface on one side of the helix and a hydrophilic surface on the opposite side.

[0314] Subsequently, additional peptide designs were generated, maintaining a total length of approximately 10 amino acid residues, but expanding the possible number of amino acid residues in the hydrophilic or hydrophobic modules from two to three and altering the hydrophobic-to-hydrophilic ratio. For example, coupling a larger hydrophobic module with three hydrophobic amino acid residues to a shorter hydrophilic module with one hydrophilic amino acid residue produced a peptide predicted to have a stronger hydrophobic character. Such peptides are predicted to maintain an amphiphilic helical secondary structure, but with a larger hydrophobic surface on one side of the helix and a correspondingly smaller hydrophilic surface on the other side. Similarly, coupling a larger hydrophilic module with three hydrophilic amino acid residues to a shorter hydrophobic module with one hydrophobic amino acid residue produced a peptide predicted to have a stronger hydrophilic character. Such peptides are also predicted to maintain an amphiphilic helical secondary structure, but with a larger hydrophilic surface on one side of the helix and a correspondingly smaller hydrophobic surface on the other side.

[0315] Other peptide designs include: peptides with modules of four or five hydrophilic amino acid residues and / or modules of four or five hydrophobic amino acid residues; peptides with a total length of about 10 amino acid residues but lacking hydrophobic amino acid residues; peptides with hydrophilic and hydrophobic modules each composed of a single amino acid residue; and proline-rich peptides. Finally, larger peptides incorporating two designs from the smaller peptide designs were also generated.

[0316] Exemplary peptides designed as described above are presented in Tables 3-9 below. To make the types of peptides developed clearer, each peptide is divided into several categories. Typically, peptides in a particular category share a common sequence of at least six or seven amino acid residues in length between the hydrophobic and hydrophilic modules in their banded hydrophobic and hydrophilic regions. However, efforts have been made to keep such peptides in the same category because data indicate that peptides with the same sequence but opposite N-terminal to C-terminal orientations unexpectedly have similar anti-inflammatory activities. Thus, some peptides have been grouped into the same category even though the length of the common sequence between the hydrophobic and hydrophilic modules is less than six amino acid residues. In addition, some peptides have been grouped differently because they contain the common sequence between the hydrophobic and hydrophilic modules of more than one category. Therefore, while providing a useful framework for grouping peptides around structural and functional similarities, the classification system does not capture all aspects of the relationships between different peptides.

[0317] Table 3 presents sequences containing the corresponding Equation I (i.e., Y). 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c Various class I polypeptides exhibit banded affinity regions. Table 3 presents two different types of class I polypeptides: those with sequences corresponding to formula II (i.e., Y). 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c -X 2a -Y 3a -X 3a Peptides consisting of banded affinity regions composed of sequences corresponding to Formula III (i.e., X) 2a -Y 3a -X 3a -Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c Peptides with banded affinity regions consisting of ) are also presented. In addition, peptides having banded affinity regions containing sequences corresponding to Formula I but not Formula II or Formula III are also presented.

[0318] Table 3: Class I polypeptides

[0319]

[0320]

[0321] Table 4 presents some pseudo-class I peptides. These peptides contain banding sequences of formula II (i.e., Y). 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c -X 2a -Y 3a -X 3a Similar sequences, but all hydrophobic amino acid residues are replaced by specific hydrophilic amino acid residues.

[0322] Table 4: Class I pseudo-peptides

[0323]

[0324] *These peptides do not conform to the sequence requirements of Formula II, but rather represent “all hydrophilicity” variations with respect to the sequence requirements of Formula II.

[0325] Table 5 presents various class II subclass 1 peptides. The peptides presented have sequences corresponding to formula X (i.e., Y). 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a -X 3a The banded regions of affinity or intimacy are composed of the sequences corresponding to Equation XI (i.e., X). 1a -Y 1a -X 2a -X 2b -Y 2a -Y 2b -X 3a -X 3b -Y 3a -Y 3b The banded regions of affinity and unfamiliarity are composed of )

[0326] Table 5: Class II Subclass 1 Polypeptides

[0327]

[0328]

[0329] Table 6 presents peptides belonging to various categories, including: Class II peptides (having banding regions containing sequences corresponding to any one of Formulas VI to XVI); Class II Subclass 2 (having banding regions containing sequences corresponding to Formulas VIII and XII); Class II Subclass 3 (having banding regions containing sequences corresponding to Formula IX); Class II Subclass 4 (having banding regions containing sequences corresponding to Formulas XIV and XV); Class II Subclass 5 (having banding regions containing sequences corresponding to Formulas XIII and XVI); Class III peptides (having banding regions containing sequences corresponding to any one of Formulas XVII to XX); Class III Subclass 1 peptides (having banding regions containing sequences corresponding to Formulas XIX or XX); Class IV peptides (having banding regions containing sequences corresponding to Formulas IV and V); Class V peptides (having banding regions containing sequences corresponding to...) The following are the types of peptides: (1) peptides containing the band affinity regions corresponding to the sequences of Formula XXI; (2) peptides containing the band affinity regions corresponding to the sequences of Formulas XXII and XXIII; (3) peptides containing the band affinity regions corresponding to the sequences of Formulas XXIV to XXVI; (4) peptides containing the band affinity regions corresponding to the sequences of Formulas XXVII to XXXII; (5) peptides containing the band affinity regions corresponding to the sequences of Formulas XXXI and XXXII, respectively; (6) peptides containing the band affinity regions corresponding to the sequences of Formulas XXXIII to XXXVIII; (7) peptides containing the band affinity regions corresponding to the sequences of Formulas XXXVII and XXXVIII, respectively; and (8) peptides containing the band affinity regions corresponding to the sequences of Formula L. Because the peptides of class VIII subclass 3 and class IX subclass 3 share the same sequences of hydrophobic and hydrophilic modules, but share opposite N-terminal to C-terminal orientations, they have been grouped into the same class and subclass. Similarly, because the peptides of class VIII subclass 4 and class IX subclass 4 share the same sequences of hydrophobic and hydrophilic modules, but share opposite N-terminal to C-terminal orientations, they have been grouped into the same class and subclass.

[0330] Table 6: Class II to IX and XIII peptides

[0331]

[0332]

[0333] Table 7 presents peptides from classes VIII to XI. All peptides presented in Table 7 have banded affinity / reluctance regions containing a hydrophilic module (having four or five hydrophilic amino acid residues) and / or a hydrophobic module (having four or five hydrophobic amino acid residues). Class VIII 1 sub-peptides have banded affinity / reluctance regions containing sequences corresponding to formula XXVIII or XXIX; Class VIII 2 sub-peptides have banded affinity / reluctance regions containing sequences corresponding to formula XXX; Class IX 1 sub-peptides have banded affinity / reluctance regions containing sequences corresponding to formula XXXIV or XXXV; Class IX 2 sub-peptides have banded affinity / reluctance regions containing sequences corresponding to formula XXXVI; Class X peptides have banded affinity / reluctance regions containing sequences corresponding to any one of formulas XXXIX to XLIII; and Class XI peptides have banded affinity / reluctance regions containing sequences corresponding to any one of formulas XLIV to XLVIII. Because peptides in subclass VIII1 and subclass IX1 share the same sequences of hydrophobic and hydrophilic modules, but share opposite N-terminal to C-terminal orientations, they have been grouped into the same class and subclass. Similarly, because peptides in subclass VIII2 and subclass IX2 share the same sequences of hydrophobic and hydrophilic modules, but share opposite N-terminal to C-terminal orientations, they have been grouped into the same class and subclass.

[0334] Table 7: Class VIII to XI peptides

[0335]

[0336] Table 8 presents polypeptides from class XII to class XIV. Class XII polypeptides contain a sequence corresponding to formula XLIX (i.e., Y...). 1a -X 1a -Y 2a -X 2a -Y 3a -X 3a The XII class peptides are predicted to employ a β-chain secondary structure. The XIV class peptides are proline-rich peptides containing banded regions of varying affinity corresponding to one of the formulas LI-LIV.

[0337] Table 8: β-chain and proline-rich peptides

[0338]

[0339] Table 9 presents fusion peptides, which comprise combinations of class I, II, and / or III peptides linked together by peptide bonds and optionally short peptide linkers (e.g., triglycine (GGG) linkers).

[0340] Table 9: Peptide Combinations

[0341]

[0342]

[0343]

[0344] In each of the tables 3-9, RP# is an indication of random assignment used to identify a specific peptide sequence. “Binding E” (see column 3 of each table) corresponds to the expected measurement of the energy released when an individual peptide binds to the protein dimer domain of the NFkB class II protein RelB (see Example 2 below).

[0345] Example 2: Predicted binding of peptide to Rel B

[0346] To identify peptides with anti-inflammatory activity, the NF-κB complex was chosen as a target because it is known to be a key component in the signaling pathways regulating inflammation. NF-κB dimerization (homogeneous or heteromeric) mediated by dimerizing domains visible in NF-κB class II proteins (e.g., RelA, RelB, cRel, NF-κB1, and NF-κB2) is essential for the activation of the NF-κB complex and the generation of pro-inflammatory signaling. Therefore, peptide design was based on the ability of the peptide to specifically bind to the dimerizing domain of RelB (NCBI accession number NP_033072.2), with the aim that such binding would inhibit NF-κB dimerization and activation.

[0347] Using the web-based ClusPro developed at Boston University in the computer. TM Algorithms evaluate the binding of peptides to the dimer domains of Rel B. ClusPro TM The algorithm filters docking conformations between protein targets and putative ligands and determines surface complementarity, thereby classifying conformations based on clustering properties. A free energy filter selects complexes with the lowest desolvation and electrostatic energies. Then, clustering lubrication local minima are used to select the complex with the broadest potential well, a property related to the free energy at the binding site. Using this method, the affinity of ligands for specific targets can be evaluated after ligand classification and subsequent testing of in vitro or in vivo biological activity.

[0348] For each peptide in the third column of Table 3-9, the results are shown via ClusPro. TMBinding energies calculated by the algorithm. In each of the tables 3-9, peptides are graded from highest to lowest binding energy based on the calculated RelB binding energies. The structure-function relationship of peptides is explored using RelB binding energies, particularly regarding (i) increasing or decreasing hydrophobicity, (ii) positive / negative charge density, and (iii) altering the curvature of the hydrophobic and hydrophilic surfaces of the peptides. The peptides shown in Table 10 (below) will be used to illustrate the results.

[0349] Table 10: Predicted binding of selected peptides to RelB

[0350]

[0351] The lower the energy value, the greater the affinity of the ligand for the binding site on the target protein.

[0352] Figure 1 A structural model of the RelB subunit of NF-kBA is shown. Amino acids with dimerization sites are masked to indicate their hydrophobic or hydrophilic characteristics. Specifically, amino acid residues painted magenta are hydrophilic, while those painted blue-green are hydrophobic. Assuming that the hydrophilic and hydrophobic amino acid residues are positioned differently within the binding pocket of the dimerization domain, a banded peptide exhibiting a clearly amphiphilic secondary structure may have the potential to bind specifically to the dimerization domain binding pocket.

[0353] exist Figure 2 The secondary structure of RP-182 (SEQ ID NO:121) and its binding with RelB (SEQ ID NO:367) were modeled. As can be seen in the figure on the right, the predicted secondary structure of RP-182 has different hydrophobic and hydrophilic sides, which contain approximately equal facial curvature (see also...). Figure 9 It also exhibits high volume. In summary, RP-182 possesses a structure with high hydrophobicity and high cationicity (it contains a total of five cationic amino acid residues). These characteristics of RP-182 are summarized in Table 11 below. Based on structural modeling, RP-182 binds to the RelB dimer domain binding bag with high affinity, where the estimated binding energy is -944.8 kcal / mol.

[0354] exist Figure 3 The secondary structure of RP-166 (SEQ ID NO:112) and its binding with RelB (SEQ ID NO:367) were modeled. As can be seen in the figure on the right, the predicted secondary structure of RP-166 also has different hydrophobic and hydrophilic sides, which contain approximately equal facial curvature (see also...). Figure 9These characteristics are not unexpected, as the banded affinity regions of RP-166 have the same (even opposite) modular structure as RP-182 (compare formulas X and XI). Like RP-182, RP-166 has high volumes of both hydrophobic and hydrophilic surfaces, but RP-166 has a larger ratio of hydrophobic to hydrophilic volume compared to RP-182. Furthermore, the cationicity of RP-166 is significantly lower than that of RP-182, as RP-166 has an equal number of cationic and anionic amino acid residues. These characteristics of RP-166 are summarized in Table 11 below. Based on structural modeling, RP-166 even binds to the RelB dimer domain binding bag with a higher affinity than RP-182, with an estimated binding energy of -1,044.8 kcal / mol.

[0355] exist Figure 4 The secondary structure of RP-113 (SEQ ID NO:39) and its binding with RelB (SEQ ID NO:367) were modeled. As can be seen in the right-hand figure, the predicted secondary structure of RP-113 also has different hydrophobic and hydrophilic sides, but the hydrophobic side contains a much larger facial curvature than the hydrophilic side. Figure 9 As shown, the facial curvature of the polar side of RP-113 is only 60°, while that of the non-polar side is 300°. Consistent with this shift toward a larger hydrophobic surface, RP-113 has a larger hydrophobic volume and a significantly larger ratio of hydrophobic to hydrophilic volume than RP-182 or RP-166. See Table 11 below. Like RP-166, the cationicity of RP-113 is significantly lower than that of RP-182 because RP-113 has an equal number of cationic and anionic amino acid residues. Based on structural modeling, RP-113 even binds to the RelB dimer domain binding bag with one of the highest affinities predicted for the peptides of this invention, with an estimated binding energy of -1,208.9 kcal / mol.

[0356] exist Figure 5 The secondary structure of RP-387 (SEQ ID NO:173) and its binding with RelB (SEQ ID NO:367) were modeled. As can be seen in the right-hand figure, the predicted secondary structure of RP-387 has different hydrophobic and hydrophilic sides. However, unlike RP-113, the hydrophilic side of RP-387 contains a much larger facial curvature than the hydrophobic side. Figure 10As shown, the facial curvature of RP-387 on the polar side is only 245°, while that on the non-polar side is 115°. Consistent with this shift toward a larger hydrophilic surface, RP-387 has a smaller hydrophobic volume and a significantly smaller ratio of hydrophobic to hydrophilic volume than any of RP-182, RP-166, and RP-113. See Table 11 below. Regarding cationicity, RP-387 is similar to RP-182, with a total of five cationic amino acid residues. Based on structural modeling, RP-387 binds to the RelB dimer domain binding bag, but the binding is relatively weak, with an estimated binding energy of only -338.3 kcal / mol.

[0357] exist Figure 6 The secondary structure of RP-289 (SEQ ID NO:232) and its binding to RelB (SEQ ID NO:367) were modeled. As shown in the right-hand figure, the predicted secondary structure of RP-289 has both hydrophobic and hydrophilic sides. However, the hydrophobic side of RP-289 is one of the smallest peptides screened. Figure 9 As shown, the facial curvature of RP-289 on the polar side is only 290°, while that on the non-polar side is only 70°. Among the peptides listed in Table 11, RP-289 has the smallest hydrophobic volume and the smallest ratio of hydrophobic to hydrophilic volume. RP-289 also has the highest cationicity among the peptides listed in Table 11, with a total of seven cationic amino acid residues. Based on structural modeling, RP-289 binds to the RelB dimer domain, although much weaker than RP-182, RP-166, and RP-113, with an estimated binding energy of only -431.6 kcal / mol.

[0358] Tables 10 and 11 also identified two control peptides, NF-CONTR2 and NF-CONTR3, which are fragments of the RelB subunit of NF-κB. The sequences of NF-CONTR2 and NF-CONTR3 do not conform to any of the structural formulas I-LIII. Figure 7 The secondary structure of NF-CONTR2 (SEQ ID NO:382) and its binding with RelB (SEQ ID NO:367) were modeled. Figure 8 The secondary structure of NF-CONTR3 (SEQ ID NO:383) and its binding to RelB (SEQ ID NO:367) were modeled. It was predicted that neither peptide would employ a clear amphiphilic secondary structure throughout its entire length. Furthermore, although ClusPro... TMThe algorithm identified the binding interactions of NF-CONTR2 and NF-CONTR3 with RelB, and the binding energies were not very strong, nor did either show a preference for binding to the RelB dimer domain binding bag.

[0359] Table 11: Physical characteristics of selected peptides

[0360]

[0361] * Binding energy is expressed in kcal / mol. Volume is expressed in cubic angstroms. HPL indicates hydrophilicity; HPB indicates hydrophobicity. "tH" is the total hydrophobicity (in kcal / mol), as defined by Engleman et al. (1986), "Identifying nonpolar transbilayer helices in amino acid sequences of membrane proteins," Annu. Rev. Biophys. Bioeng. 15:321–53.

[0362] Figures 1 to 10 Table 11 reveals some important aspects of the structure-function relationship of the peptides of the present invention. First, all peptides predicted to bind to the RelB dimer domain binding bag have amphiphilic secondary structures. Second, a larger hydrophobic volume and a larger ratio of hydrophobic to hydrophilic volume are associated with increased affinity for the RelB dimer domain binding bag. Third, increased cationicity is associated with decreased binding affinity for the RelB dimer domain binding bag.

[0363] Table 4 lists some “all-hydrophilic” variants of class I peptides, which appears to potentially refute the conclusion that increased cationicity is associated with decreased binding affinity to the binding bag of the RelB dimer domain. In each peptide in Table 4, the hydrophobic residues of the class I formula II peptide have been replaced by a single type of hydrophilic residue. Importantly, both RP-173 (HHHRHHHEHQ; SEQ ID NO: 99) and RP-195 (RRRRRRRERQ; SEQ ID NO: 100) exhibit high affinity for the binding bag of the RelB dimer domain (-1,002.2 and -855.2 kcal / mol, respectively), despite having eight amino acid residues that typically have a cationic charge in solution. The potential indication that histidine and arginine have high RelB binding affinity is that the uncharged hydrocarbon groups in the side chains provide some hydrophobicity, which is further lost by the conversion of hydrophobic residues to hydrophilic residues. Furthermore, when bound to RelB, some histidine and arginine residues can be in an uncharged state. Table 4 thus further clarifies the structure-function relationship of the peptides of the present invention by indicating that histidine and arginine can act as hydrophobic-like agents (at least regarding the binding affinity of the peptide to the RelB dimerizing domain). Therefore, in some peptides of the present invention, histidine or arginine can be advantageously placed adjacent to a hydrophobic module consisting of one or two hydrophobic amino acid residues.

[0364] Example 3: RelB amino acid residues involved in peptide binding

[0365] Figure 11 A model of amino acid residues that aligns the binding pouches of the RelB dimerizing domain is shown. The model indicates that Glu-298, Asp-330, and His-332 are key hydrophilic amino acid residues that align the binding pouches, while Tyr-300, Leu-301, Leu-302, and Leu-371 are important hydrophobic residues. Figure 12 The same model is shown with the symbol diagram of RP-182 peptide (SEQ ID NO:121) added. Figure 12The dashed lines in the diagram show the ionic bonds between (1) Lys-7 of RP-183 and Asp-330 of Rel-B, and (2) Lys-4 of RP-183 and Glu-298 of Rel-B. Further stabilizing interactions are the interionic bonds formed between Arg-8 of RP-183 and Lys-10 at the carboxyl terminus of RP-183. In addition to ionic bonds, numerous van der Waals interactions exist. For clarity, only the interaction between Phe-9 of RP-182 and Leu-371 of Rel-B is shown. However, other hydrophobic amino acid residues on the hydrophobic surface of RP-183 interact with the hydrophobic “bottom” of the dimerization sites of Rel-B.

[0366] Analysis of ionic and van der Waals interactions involving the binding of different peptides of this invention revealed peptide binding to a subset of RelB amino acid residues selected from the following group: Leu-281, Ile-283, Cys-284, Glu-298, Tyr-300, Leu-301, Leu-302, Cys-303, Ile-311, Ser-312, Ala-329, Asp-330, Val-331, His-332, Gln-334, and Leu-371. See Table 13 below. Tyr-300, Leu-302, and His-332 are indicated in the literature as being critical for dimerization. The most critical amino acids for binding via the peptides of this invention include Glu-298, Tyr-300, Leu-302, Asp-330, Gln-334, and Leu-371.

[0367] Example 4: Binding of peptides to protein targets other than RelB

[0368] A subset of the peptides shown in Tables 3-9 were further evaluated in a computer to determine whether they bind to signaling proteins involved in the inflammatory response other than RelB. In doing so, it was found that the dimerization cleft of the RelB subunit of NF-κB has structural parallels in many other signaling molecules. Consistent with these structural parallels, predictions (via ClusPro) were made. TM(Algorithm) The peptides of this invention bind with high affinity to important signaling molecules in the inflammatory cascade, including: TGFβ (NCBI accession number NP_000651.3; SEQ ID NO:368); Notch1 (GenBank accession number AAG33848.1; SEQ ID NO:369); Wnt8R (NCBI accession number XP_005214377.1; SEQ ID NO:370); TRAIL (GenBank accession number EAW78466.1; SEQ ID NO:371); IL6R (NCBI accession number NP_786943.1; SEQ ID NO:372); IL10R (NCBI accession number NP_001549.2; SEQ ID NO:373); EGFR (GenBank accession number AAR85273.1; SEQ ID NO:374); and CDK6 (NCBI accession number NP_001250.1; SEQ ID NO:373). NO:375). Representative peptides of the present invention and their predicted binding energies to these signaling molecules are shown in Tables 12A and 12B below.

[0369] Table 12A: Predicted binding of selected peptides to different inflammatory targets

[0370]

[0371] *All binding affinities are expressed in kcal / mol.

[0372] Table 12A: Predicted binding of selected peptides to different inflammatory targets

[0373]

[0374] Data showed that the binding strength of RelB was highly correlated with the binding strength of different inflammatory targets. In other words, peptides predicted to bind to RelB with high affinity were also predicted to bind to TGFβ, Notch1, Wnt8R, TRAIL, EGFR, IL6R, and IL10R with high affinity.

[0375] A closer evaluation of the predicted binding interactions between the peptides of the present invention and each of TGFβ, Notch1, Wnt8R, TRAIL, EGFR, IL6R, and IL10R shows that the peptides bind not only with high affinity but also to functionally critical sites on the targets. For example, the peptides of the present invention are predicted to bind to receptor-binding sites on TGFβ, calcium-binding sites on Notch1, Wnt8-binding sites on Wnt8R, receptor-binding sites on TRAIL, IL6-binding sites on IL6R, IL10-binding sites on IL10R, and general ligand-binding sites on EGFR. Table 13 shows a non-exhaustive list of amino acid residues bound to these targets by the peptides of the present invention.

[0376] Table 13: Amino acid residues in the target protein that are contacted by the peptides of this invention

[0377]

[0378]

[0379] Assuming the existence of numerous immunologically important signaling proteins targeted by the peptides of this invention, data indicate that the peptides function in a pleiotropic manner, resulting in a broad anti-inflammatory response through numerous different interactions. This could allow for the reduction of disease conditions without the toxicity observed with more targeted chemotherapy agents.

[0380] Example 5: Binding of peptides with histone-modifying enzymes and ribonuclease reductases

[0381] Structural features of the N-terminal regions of histones shared by many peptides of the present invention have been observed. Therefore, the ability of representative peptides to bind to histone-modifying enzymes was evaluated in a computer. In this way, the peptides of the present invention were found to have high affinity for histone methyltransferase (HMT) (NCBI accession number NP_048968.1; SEQ ID NO:376), thereby binding tightly to the active site of the enzyme. Table 14 shows the predicted binding energies of selected peptides of the present invention to HMT, calculated using ClusPro. TM The algorithm is used for calculation. Moreover, the predicted binding energy correlates well with the predicted energy of binding RelB.

[0382] Table 14: Binding affinity of selected peptides to HMT, MKK7 and RNR

[0383]

[0384] *All binding affinities are expressed in kcal / mol.

[0385] Figure 13A model of a histone methyltransferase (HMT) bound by RP-182 is shown. The orange amino acids represent the active sites of the histone methyltransferase. Inhibition of the methyltransferase by RP-182 is expected because RP-182 binds to at least one residue of the active site in a manner that appears to impede access to the active site. A non-exhaustive list of amino acid residues in the HMT bound by the peptides of the present invention is shown in Table 13 above.

[0386] The peptides of the present invention were also observed to show a strong predicted affinity for MAP kinase kinase 7 (MKK7; SEQ ID NO: 417), a family of mitogen-activated protein kinase kinases involved in cellular responses mediated by signal transduction of pro-inflammatory cytokines, and therefore potentially involved in the anti-inflammatory activity of the peptides. For example, RP-182 showed a predicted affinity of -738.2 kcal / mol for MKK7.

[0387] Furthermore, the peptides of the present invention were observed to exhibit a high predicted affinity for ribonuclease reductase (RNR; SEQ ID NO:418) (also known as nucleoside diphosphate reductase). This is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. The deoxyribonucleotides are then used to synthesize DNA. Reactions catalyzed by RNR are strictly conserved in all living organisms. In addition, RNR plays a crucial role in regulating the overall rate of DNA synthesis, maintaining a constant ratio of DNA to cell mass during cell division and DNA repair. A slightly unusual characteristic of RNR enzymes is that they catalyze reactions via a free radical mechanism. The substrates of RNR are ADP, GDP, CDP, and UDP. dTDP (deoxythymidine diphosphate) is synthesized from dTMP (deoxycytidine monophosphate) via another enzyme (thymidine kinase). For example, RP-182 has a predicted affinity for RNR of -814.0 kcal / mol.

[0388] Example 6: Binding of peptides to targets associated with macrophage activation

[0389] The peptides of the present invention are also predicted to interact with several proteins associated with macrophage activity and apoptosis (properties related to inflammation and tumorigenesis and metastasis). Targets identified to date include CD47, SIRP-α, CD206, TGM2, LEGUMAIN, DC-SIGN, CSF1, CSF1R, and IL34.

[0390] CD47 (or “differentiation cluster 47”), also known as integrin-associated protein (IAP), is a transmembrane protein belonging to the immunoglobulin superfamily. The CD47 protein pairs with membrane-bound cell attachment receptors called integrins and also binds ligands platelet-reactive protein-1 (TSP-1) and signal regulatory protein α (SIRP-α). CD47 is involved in a range of cellular processes, including apoptosis, proliferation, attachment, and migration. Additionally, it plays a crucial role in immune responses and angiogenesis. CD47 is expressed in many types of human cells and has been found to be overexpressed in many different types of tumors. Overexpression of CD47 has received considerable attention as a potential human cancer protectant. By binding to SIRP-α on the surface of macrophages, CD47 is believed to send a “don’t eat me” signal that prevents macrophages from attacking cancer cells.

[0391] CD206 and TGM2 have also been identified as potentially important regulators of macrophage activity. CD206 is a C-type lectin primarily found on the surface of macrophages and dendritic cells. It is the first member of the endocytic receptor family, which includes Endo180 (CD280), M-type PLA2R, and DEC-205 (CD205). This receptor recognizes terminal mannose, N-acetylglucosamine, and fucose residues that constitute a glycan that attaches to proteins visible on the surface of some microorganisms. Therefore, the CD206 receptor appears to play a role in both the innate and adaptive immune systems. Furthermore, tumor-associated macrophages can use CD206 to digest collagen, producing degradation products that nourish both themselves and tumor cells, and weakening collagen binding in tumor cells to promote metastasis.

[0392] TGM2 belongs to a family of enzymes that catalyze calcium-dependent translational modifications of proteins. These family members are found both intracellularly and extracellularly. TGM2 is unique within this family due to its versatility and distinctive structure, comprising four distinct domains: an N-terminal β-sandwich containing fibronectin and integrin binding sites; a catalytic core containing a catalytic triad (Cys-277, His-335, and Asp-358) for acyltransferase reactions; and two C-terminal β-barrel domains, the second of which has a phospholipase-binding sequence. TGM2 participates as a regulator of extracellular matrix functions, including cell adhesion and migration, cell growth and differentiation, apoptosis, tumor growth, and wound healing. Although TGM2 is universally expressed, it is most highly expressed in M2 macrophages. Furthermore, increased TGM2 levels are associated with adverse outcomes in scleroderma, pulmonary and renal fibrosis, worsening symptoms of diabetes, arthritis and EAE, and many different cancers, all of which can be associated with M2 macrophages.

[0393] Table 15 shows the usage of ClusPro TM The algorithm calculated the predicted binding energies of the selected peptides of this invention for CD47 (NCBI accession number XP_005247966.1; SEQ ID NO:377), SIRP-α (GenBank accession number AAH26692.1; SEQ ID NO:378), CD206 (NCBI accession number NP_002429.1; SEQ ID NO:379), and TGM2 (GenBank accession number AAB95430.1; SEQ ID NO:380). As with the other targets discussed above, the predicted binding energies correlated well with the predicted energies for RelB binding.

[0394] LEGUMAIN is a protein encoded by the LGMN gene in humans. This gene encodes a cysteine ​​protease, a pod protein with strict specificity for the hydrolysis of asparagine bonds. This enzyme is involved in the processing of MHC class II presented bacterial peptides and endogenous proteins in the lysosomal / endosome system. Enzyme activation is triggered by acidic pH and appears to be autocatalytic. Protein expression occurs after monocytes differentiate into dendritic cells. Fully mature, active enzyme is produced following lipopolysaccharide expression in mature dendritic cells. Overexpression of this gene is likely associated with most solid tumor types. LEGUMAIN is also overexpressed in M2 macrophages and is expected to downregulate the activity of M2-activated macrophages by inhibiting its activity through the disclosed peptide.

[0395] DC-SIGN (dendritic cell-specific intracellular adhesion molecule-3-grasp non-integrin), also known as CD209 (differentiation cluster 209), is a protein encoded by the CD209 gene in humans. DC-SIGN is a C-type lectin receptor found on the surface of both macrophages and dendritic cells. On macrophages, DC-SIGN recognizes and binds to mannose-type carbohydrates, a class of pathogen-associated molecular patterns (PAMPs) commonly found on viruses, bacteria, and fungi. This binding interaction activates phagocytosis. On myeloid and preplasmacytic dendritic cells, DC-SIGN mediates the rolling interaction between dendritic cells and blood endothelial cells, CD4+ T cell activation, and the recognition of pathogen haptens. DC-SIGN is significantly overexpressed in M2 macrophages, and inhibition of its activity via the disclosed peptide is expected to downregulate M2-activated macrophages.

[0396] Table 15: Binding affinity of selected peptides to CD47, SIRP-α, CD206, and TGM2

[0397]

[0398] *All binding affinities are expressed in kcal / mol.

[0399] Figure 14 (Left figure) shows a model of the extracellular domain of CD47 dimer (top view) (SEQ ID NO:377), where the magenta and blue-green surfaces represent polar and nonpolar amino acids, respectively, which are involved in the binding of CD47 to the SIRP-α receptor. Figure 14 (Right figure) shows a model of the extracellular domain of the CD47 dimer when bound by RP-183 (SEQ ID NO: 121). Based on this predicted interaction between RP-183 and CD47, the peptide of the present invention is expected to block the interaction between CD47 and SIRP-α.

[0400] Figure 15 A model of the SIRP-α dimer (SEQ ID NO: 378) is shown, where the magenta and blue-green surfaces represent the polar and nonpolar amino acids involved in its binding to CD47 (see the leftmost dimer), respectively. In a slightly tilted view of the same SIRP-α dimer bound by RP-183 (SEQ ID NO: 122) (see the rightmost dimer), it can be seen that RP-183 is tightly bound to the amino acids involved in binding to the CD47 receptor. Therefore, it is clear that RP-183 (and other peptides of the present invention) binds to corresponding binding sites of both CD47 and SIRP-α through two different mechanisms to block the interaction between CD47 and SIRP-α. Thus, the predicted activities associated with the peptides of the present invention include blocking important defense mechanisms against cancer cells.

[0401] The invention also predicts key sites on the CD206 receptor subunit that the peptide blocks. Figure 16 A model of CD206 (SEQ ID NO: 379) bound by RP-182 (SEQ ID NO: 121) is shown. Blue-green tyrosine residues on the curved region of CD206 (leftmost molecule) interact with mannose ligands on the target cell surface, forming a planar hydrophobic stack. Magenta amino acids contribute to the chelation of acidic residues containing calcium ions required for stable interaction with the mannose receptor. The RP-182 peptide (visible in the pores on the rightmost molecule) blocks activity by interacting with two of these key sites on the receptor subunit. Therefore, the peptide of the present invention is expected to reduce the viability of M2 macrophages, which has been experimentally confirmed (as listed below).

[0402] Furthermore, it is predicted that the peptide of the present invention blocks the active site of TGM2. Figure 17 (Left figure) shows a model of TGM2 (SEQ ID NO:380) with active site residues highlighted in blue. Figure 17 (Right figure) shows the same model of TGM2 bound by RP-182 (SEQ ID NO: 121), which is magenta. As can be seen, RP-182 is predicted to bind to TGM2 in a manner that completely covers the active site, thereby hindering substrate access and inhibiting TGM2 function. Importantly, reduced TGM2 levels are associated with decreased NF-κB activation; therefore, the interaction of the peptides of the present invention with TGM2 will exhibit an inhibitory effect that enhances and / or amplifies their NF-κB activity.

[0403] Table 13 above shows a non-exhaustive list of specific amino acid residues bound by the peptides of the present invention in CD47, SIRP-α, CD206, and TGM2.

[0404] Example 7: Binding of peptides to checkpoint inhibitors and related targets

[0405] The peptides of the present invention have also been observed to exhibit high affinity for checkpoint inhibitor proteins and their ligands. Such proteins, expressed on the surface of effector immune cells (including cytotoxic T-lymphocyte antigen 4 (CTLA-4), PD-1, and other inhibitory co-receptors), appear to deplete the activity of immune cells upon activation, thus acting as immune checkpoints to prevent uncontrolled immune responses. Tumor cells often express ligands of checkpoint inhibitors such as PD-L1 and PD-L2, thereby weakening the immune system's ability to attack tumors.

[0406] Specifically, programmed cell death protein 1, also known as PD-1 and CD279 (differentiation cluster 279), is a protein encoded by the PDCD1 gene in humans. PD-1 is a cell surface receptor belonging to the immunoglobulin superfamily and is expressed on T cells and B-cells. PD-1 binds to two ligands, PD-L1 and PD-L2. PD-1 acts as an immune checkpoint, playing a crucial role in downregulating the immune system by preventing T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is achieved through a dual mechanism: promoting apoptosis (programmed cell death) in antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressive T cells).

[0407] Programmed death-ligand 1 (PD-L1), also known as differentiation cluster 274 (CD274) or B7 homolog 1 (B7-H1), is a protein encoded by the CD274 gene in humans. PD-L1 is a 40 kDa type 1 transmembrane protein that has been presumed to play a major role in suppressing the immune system during specific events such as pregnancy, tissue allogeneic transplantation, autoimmune diseases, and other disease states such as hepatitis. Normally, the immune system responds to foreign antigens, with some accumulation of antigen-specific CD8+ T cells occurring in lymph nodes or the spleen. The formation and transmission of PD-1 receptor / PD-L1 or B7.1 receptor / PD-L1 ligand complexes reduce the proliferation of these CD8+ T cells in lymph nodes and provide additional inhibitory signals: PD-1 can also control the accumulation of foreign antigen-specific T cells in lymph nodes through apoptosis, which is further mediated by the downregulation of the Bcl-2 gene.

[0408] Based on the illustration of the binding of the peptides of the present invention to checkpoint inhibitors and their ligands, RP-182 has a predicted affinity of -742.9 for PD-1, and RP-621 has a predicted affinity of -1,008.8. RP-182 has an affinity of -677.4 for PD-L1, and RP-621 has an affinity of -1,010.6 for PD-L1. Similar to inflammatory targets, significant correlations exist within the predicted affinities for several other checkpoint inhibitors and their ligands, as well as with other proteins known to play a role in regulating immune organs. These include: TIM-1 (believed to play a role in T-helper cell development: predicted affinity for RP-182 -850.1); CTLA-4 (checkpoint inhibitor: predicted affinity for RP-182 -663.2); ADORA2a (regulates neutrophil and mast cell activity: predicted affinity for RP-182 -938.7); OX40 (secondary co-stimulatory immune checkpoint: predicted affinity for RP-182 -759.9); IDO (immune checkpoint: predicted affinity for RP-182 -934.0); LAG-3 (immune checkpoint receptor: predicted affinity for RP-182 -873.1); CD73 (restricts T-cell activity via adenosine receptor signaling). Enzymes involved in cell activity: CD73-I (predicted affinity for RP-182: -808.7; CD73-II (predicted affinity for RP-182: -949.1); arginase-1 (blocks cytotoxic T lymphocyte activity: predicted affinity for RP-182: -984.2); colony-stimulating factor 1 (upregulates the indicated blockade of checkpoint molecules and resets macrophage responses; CSF1 (predicted affinity for RP-182: -854.7; CSF1D (predicted affinity for RP-182: -847.1; CSF1R (predicted affinity for RP-182: -774.1); and IL34 (also activates CSF1R: predicted affinity for RP-182: -828.5).

[0409] Example 8: Binding of peptide to MKK7

[0410] Bispecific mitogen-activated protein kinase 7 (MKK7), also known as MAP kinase 7 or MKK7, is an enzyme encoded by the MAP2K7 gene in humans. This protein is a member of the mitogen-activated protein kinase kinase family. MKK7 exists as six distinct isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (I and II isoforms). MKK7 is involved in signal transduction mediating cellular responses to pro-inflammatory cytokines and environmental stress. This kinase specifically activates MAPK8 / JNK1 and MAPK9 / JNK2, and the kinase itself is phosphorylated and activated by MAP kinase kinases, including MAP3K1 / MEKK1, MAP3K2 / MEKK2, MAP3K3 / MEKK5, and MAP4K2 / GCK.

[0411] Example 9: Binding of peptides to serum albumin

[0412] It is well known that serum albumin is the most abundant protein in circulation. It is also known that solid tumors take up serum albumin into their cells (through endocytosis) and use it as an energy source. Therefore, the ability of the peptides of the present invention to bind to human serum albumin (HSA) (NCBI Acc.No. NP_000468.1; SEQ ID NO:381) was evaluated in a computer. The peptides of the present invention were found to have the ability to bind to HSA with high affinity. The predicted binding energies of selected peptides of the present invention to HSA are shown in Table 16 below.

[0413] Table 16: Binding affinity of selected peptides to human serum albumin (HSA)

[0414]

[0415] *All binding affinities are expressed in kcal / mol.

[0416] Figure 18 A model of HSA (shown in green) bound by RP-183 (blue). Computational modeling has identified numerous possible peptide binding sites on the HSA. Therefore, it is believed that a single HSA molecule can bind to multiple peptides of the present invention. The binding interactions between the peptides of the present invention and HSA indicate that HSA can be used as an in vivo carrier for peptides. In this way, HSA can protect peptides from degradation in the blood and carry peptides to sites of action, such as sites of inflammation and / or cancer cells, thereby increasing the efficacy of the peptides.

[0417] Example 10: In vitro regulation of NF-κB activity

[0418] NF-κB activity was monitored using 3T3-L1 preadipocyte cell lines stably transformed with the Nfkb-RE / GFP construct, as described in Shen et al. (2013), “Adipocyte reporter assays: Application for identification of anti-inflammatory and antioxidant properties of mangosteen xanthones,” Mol. Nutr. Food Res. 00:1-9, the entire contents of which are incorporated herein by reference. NF-κB-expressing adipocyte reporter cells were seeded in DMEM at a density of 5 x 10⁶ cells / well in 24-well plates. 4 On days two and three after plating, the test peptides were added individually to the wells at a final concentration of .01 μM. The test peptides included RP-398 (SEQ ID NO:155) and RP-185 (SEQ ID NO:123). On day four after plating, lipopolysaccharide was added to the culture medium at a final concentration of 20 ng / ml. Finally, on day five after plating, cells were harvested and fluorescence assays were performed to detect GFP expression levels.

[0419] In this experiment, NF-κB expression was reduced by approximately 58% compared to control cells not exposed to RP-398 or RP-185 peptides.

[0420] Example 11: In vivo regulation of macrophage activity

[0421] A frequently observed phenotype associated with tumorigenesis and metastasis is the polarization of macrophages into an "M2" transitional state, in which they are in an inflammatory state. These macrophages are those denoted as "tumor-associated macrophages" (TAMs). To determine whether the peptides of the present invention can affect macrophage polarization, the following experiments were performed.

[0422] Primary bone marrow cells were collected from male C57BL / 6J mice (The Jackson Laboratory, Bar Harbor, ME). Mouse bone marrow macrophages were differentiated from primary bone marrow cells in vitro by culturing them for 6 days in Dulbecco minimum essential medium (DMEM) containing 10% FBS and 30 ng / ml murine M-CSF (colony-stimulating factor). On day 7, macrophages were plated into 12-well plates and cultured for 24 hours in DMEM (10% FBS) containing (i) IL-4 peptide (20 ng / mL), (ii) INF-γ (10 ng / mL), or (iii) neither IL-4 nor INF-γ. After 24 hours, the medium was replaced with pure DMEM and the cells were cultured for another 48 hours. The resulting macrophages were then classified as (i) M2-polarized, (ii) M1-polarized, or (iii) undifferentiated.

[0423] Macrophage samples containing approximately 70,000 undifferentiated macrophages per ml were incubated with 100 nM RP-182 (SEQ ID NO: 121) for 72 hours. Following incubation, viable cell counts showed 68,000 cells per ml. Similarly, incubation of M1-polarized macrophages with 100 nM RP-182 for 72 hours yielded a viable cell count of 68,000 cells per ml. Therefore, RP-182 had almost no effect on the viability of M1 macrophages. In contrast, incubation of M2-polarized macrophages with 100 nM RP-182 for 72 hours yielded a viable cell count of only 20,000 cells per ml. These results indicate that RP-182 reduces the viability of M2 macrophages.

[0424] Example 12: Downregulation of checkpoint inhibitors and ligands

[0425] The peptides of the present invention were also evaluated based on their predicted affinity for checkpoint inhibitors (e.g., PD-1) and their ligands (e.g., PD-L1 and PD-L2) to determine whether the concentrations of these proteins in treated tissues would be downregulated in vivo. In one experiment, tumors in transgenic p53 / KRAS mice were allowed to grow to approximately 100 m³ in volume. 3 And then, animals were subcutaneously treated once daily for one week with either a medium or 10 mg / kg RP-182, after which the animals were sacrificed and the tumors were excised, fixed in formalin, and treated with PD-1 ( Figure 19 ), PD-L1 and PD-L2 Figure 20 Antibody staining. As can be clearly seen from the figure, the checkpoint inhibitor PD-1 and its ligands PD-L1 and PD-L2 are significantly downregulated in vivo in tissues treated with the peptides of this disclosure.

[0426] Example 13: Inhibition of tumor growth

[0427] The effect of the peptides of this invention on tumor growth in a mouse model of non-metastatic breast cancer was also tested. MCF-7 human non-metastatic breast cancer cells were incubated in normal growth medium at 37°C and 5% CO2. Cells were harvested at 80% to 90% confluence. Immunocompromised athymic nude mice (J:NU) were divided into two groups (n=9 per group). ~4.5 x 10⁻⁶ cells were used. 6 MCF-7 cells, stained with VIVO Tracker 680 and suspended in 200 μl of PBS / Matrigel mixture, were injected into all mice. The cells were subcutaneously injected into the dorsal side of the treated animals using a 22-gauge needle equipped with a 500 μl syringe.

[0428] Animals were administered the medium and peptide treatment. Peptide-treated animals were treated with the RP-397 peptide (SEQ ID NO: 194). Freshly prepared RP-397 peptide was dissolved in sterile saline at a concentration of 100 μM and used to treat the peptide group of animals. Animals treated with the medium were injected using saline-buffered saline alone. All treatments were administered using a 27-inch syringe equipped with a 1 ml syringe. 1 Tumor material was injected twice weekly using a No. 2 needle for 5 weeks. Animal body weight and tumor volume were measured three times weekly and fluorescently labeled, followed by VIVO Tracker 680 and IVIS imaging. The results are shown in Table 17 below.

[0429] Table 17: Tumor growth inhibition using RP-397

[0430]

[0431] Tumor growth rate in mm 3 Measurements are taken on a daily basis. "*" indicates a statistically significant difference compared to the control group.

[0432] Data shows that the peptides of this invention can inhibit tumor growth in vivo.

[0433] Example 14: Combination of peptide administration and chemotherapy

[0434] Assuming that inflammation plays an important role in tumorigenesis and metastasis, and that M2 macrophage activity is known to be associated with tumor development, it is anticipated that administration of the peptides of the present invention could advantageously influence cancer treatment outcomes.

[0435] To test this theory, ~5x10 was used below the upper left nipple. 6Groups of mice were injected with individual triple-negative breast cancer cells (MDA-MB-231) into immunocompromised (“naked”) mice. Following this administration, one group received the carrier only; two groups received the chemotherapy agent gemcitabine at a dose of 40 mg / kg body weight every 4 days. One of these groups also received RP-182 (SEQ ID NO:121) at a daily dose of 5 mg / kg body weight; and a fourth group received RP-182 at a daily dose of 5 mg / kg body weight only. At the start of day 32 of the study, in the gemcitabine + RP-182 group, the concentration of RP-182 was increased to 20 mg / kg body weight. Tumor volume was assessed at different time points following the initial cell administration. Figure 21 The mice were euthanized after 50 days.

[0436] Data showed that treatment with a combination of gemcitabine and the peptide of this invention resulted in a reduction in mean tumor volume compared to treatment with gemcitabine alone. The increase in tumor volume substantially ceased when the RP-182 concentration was increased to 20 mg / kg body weight.

[0437] In the second experiment, xenografts of C42B prostate cancer cells were introduced into four mouse groups, and the tumors were allowed to grow to approximately 100 m² before treatment. 3 One group was treated with the medium alone; the second group was treated with docetaxel at 2.5 mg / kg body weight once weekly; the third group was treated with RP-182 at 10 mg / kg body weight subcutaneously daily; and the fourth group was treated with both docetaxel at 2.5 mg / kg body weight once weekly and RP-182 at 10 mg / kg body weight once daily. Tumor volume was assessed at different time points after initial cell administration. Figure 22 Mice were sacrificed after 27 days. Similarly, administration of RP-182 plus docetaxel resulted in a reduction in mean tumor volume compared to docetaxel alone.

[0438] The peptides of the present invention are expected to produce synergistic effects when administered in combination with chemotherapy agents other than gemcitabine and docetaxel, as well as checkpoint inhibitor therapies and other immunotherapies. Specifically, the peptides of the present invention may be particularly useful when used in conjunction with recently developed CAR-T (chimeric antigen receptor / T-cell) therapies. Such therapies generate a very high systemic load of dead cells while destroying tumor cells, thereby overstimulating the immune system and producing a potentially fatal "cytokine storm" in patients.

[0439] Implementation Plan

[0440] The following embodiments are provided to illustrate various aspects of the present invention.

[0441] 1. An anti-inflammatory composition comprising a peptide, wherein the peptide has a length of 3 to 24 amino acid residues and comprises alternating X... m Module and Y n The striped region of affinity consists of modules, where m and n are positive integers that distinguish different modules, and each X m The module is based on formula X ma -X mb -X mc -X md -X me The sequence consists of X ma Select the group consisting of naturally occurring hydrophilic amino acids, non-naturally occurring hydrophilic amino acids, and hydrophilic amino acid mimics, wherein X mb X mc X md and X me Each Y is individually absent or selected from groups consisting of naturally occurring hydrophilic amino acids, non-naturally occurring hydrophilic amino acids, and hydrophilic amino acid mimics, wherein each Y n The module is based on formula Y na -Y nb -Y nc -Y nd -Y ne The sequence consists of Y na The group consisting of naturally occurring hydrophobic amino acids, non-naturally occurring hydrophobic amino acids, and hydrophobic amino acid mimics was selected, among which Y... nb Y nc Y nd and Y ne Each of the following groups consists of naturally occurring hydrophobic amino acids, non-naturally occurring hydrophobic amino acids, and hydrophobic amino acid mimics, and wherein the peptide binds to a dimerizing site on an NFkB class II protein.

[0442] 2. The anti-inflammatory composition as described in embodiment 1, wherein each X m The module is based on formula X ma -X mb -X mc -X md The sequence consists of, and each Y n The module is based on formula Y na -Y nb -Y nc -Y nd The sequence composition.

[0443] 3. The anti-inflammatory composition as described in embodiment 1, wherein each X m The module is based on formula X ma -X mb-X mc The sequence consists of, and each Y n The module is based on formula Y na -Y nb -Y nc The sequence composition.

[0444] 4. The anti-inflammatory composition as described in any one of embodiments 1 to 3, wherein the peptide is further bound to human serum albumin.

[0445] 5. The anti-inflammatory composition according to any one of embodiments 1 to 4, wherein the band-like affinity region of the peptide contains at least two X's. m Modules (X1, X2, and X3) and at least two Y n Modules (Y1, Y2, and Y3).

[0446] 6. The anti-inflammatory composition according to any one of embodiments 1 to 5, wherein the banded affinity region of the peptide contains at least seven amino acid residues.

[0447] 7. The anti-inflammatory composition according to any one of embodiments 1 to 6, wherein the banded affinity region of the peptide has a length of 7 to 12 amino acid residues.

[0448] 8. The anti-inflammatory composition according to any one of embodiments 1 to 7, wherein the banded affinity region of the peptide constitutes at least 25% of the length of the peptide.

[0449] 9. The anti-inflammatory composition according to any one of embodiments 1 to 8, wherein the banded affinity region of the peptide has an amphiphilic conformation under physiological conditions.

[0450] 10. The anti-inflammatory composition of embodiment 9, wherein the band-like affinity region of the peptide is amphiphilic when bound to NF-κB class II proteins. 10 - Helical conformation, amphiphilic α-helical conformation, or amphiphilic π-helical conformation.

[0451] 11. The anti-inflammatory composition as described in embodiment 10, wherein the amphiphilic 3 10 - Helical, α-helical, or π-helical conformations contain a hydrophobic portion having a facial curvature of at least 100°.

[0452] 12. The anti-inflammatory composition according to any one of embodiments 1 to 11, wherein the banded affinity region contains hydrophobic amino acid residues with a total volume of at least 650 cubic angstroms.

[0453] 13. The anti-inflammatory composition according to any one of embodiments 1 to 12, wherein the banded hydrophobic and hydrophilic regions are characterized by a ratio of the sum of the volumes of hydrophobic amino acid residues to the sum of the volumes of hydrophilic amino acid residues, wherein the ratio is at least 0.75 or higher.

[0454] 14. The anti-inflammatory composition of embodiment 9, wherein the banded affinity region of the peptide comprises at least one proline residue and is in an amphiphilic conformation comprising a proline-rich helix.

[0455] 15. The anti-inflammatory composition as described in embodiment 9, wherein the banded affinity region of the peptide adopts an amphiphilic β-chain conformation.

[0456] 16. The anti-inflammatory composition according to any one of embodiments 1 to 13, wherein the band-like affinity region comprises a sequence selected from the group of sequences defined by formula I: Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula I).

[0457] 17. The anti-inflammatory composition as described in embodiment 16, wherein module Y 1a -Y 2b -Y 2c The sequences selected from the following groups are: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III).

[0458] 18. The anti-inflammatory composition as described in embodiment 16, wherein module Y 1a -Y 1b -Y 1c Sequences with groups selected from the following: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), and Tyr-Tyr-Tyr (YYY).

[0459] 19. The anti-inflammatory composition according to any one of embodiments 16 to 18, wherein the module Y 2a -Y 2b -Y 2cThe sequences selected from the following groups are: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III).

[0460] 20. The anti-inflammatory composition according to any one of embodiments 16 to 18, wherein the module Y 2a -Y 2b -Y 2c Sequences with groups selected from the following: Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), and Tyr-Tyr-Tyr (YYY).

[0461] 21. The anti-inflammatory composition of embodiment 16, wherein the band-like affinity region comprises a sequence selected from the group consisting of: FFF-X 1a -FFF(SEQ ID NO:1), WWW-X 1a -WWW(SEQ ID NO:2) and YYY-X 1a -YYY(SEQ ID NO:3).

[0462] 22. The anti-inflammatory composition as described in embodiment 16, wherein the sequence of the three modules is selected from the group consisting of: LLL-X 1a -LLL(SEQ ID NO:4), CCC-X 1a -CCC(SEQ ID NO:5), MMM-X 1a -MMM(SEQ ID NO:6), VVV-X 1a -VVV (SEQ ID NO:7) and III-X 1a -III(SEQ ID NO:8).

[0463] 23. The anti-inflammatory composition according to any one of embodiments 16 to 22, wherein X 1a Choose from the following groups: Arg(R), His(H), and Lys(K).

[0464] 24. The anti-inflammatory composition according to any one of embodiments 16 to 22, wherein X 1a Choose from the following groups: Glu (E), Gln (Q), Asn (N), and Asp (D).

[0465] 25. The anti-inflammatory composition according to any one of embodiments 16 to 24, wherein the band-like affinity region comprises a sequence selected from the group of sequences defined by Formula II or the group of sequences defined by Formula III: Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c -X 2a -Y 3a -X 3a (Formula II); X 2a -Y 3a -X 3a -Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula III)

[0466] 26. The anti-inflammatory composition as described in embodiment 25, wherein X 2a and X 3a Select individually from the following groups: Arg(R), His(H), Lys(K), Glu(E), Gln(Q), Asn(N), and Asp(D).

[0467] 27. The anti-inflammatory composition as described in embodiment 25, wherein X 2a and X 3a Each of the following groups is selected individually: Glu (E), Gln (Q), Asn (N), and Asp (D).

[0468] 28. The anti-inflammatory composition as described in any one of embodiments 25 to 27, wherein Y 3a Choose from the following groups: Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), and Ile (I).

[0469] 29. The anti-inflammatory composition according to any one of embodiments 25 to 27, wherein Y 3a Choose from the following groups: Phe (F), Trp (W), Tyr (Y), and Leu (L).

[0470] 30. The anti-inflammatory composition as described in embodiment 25, wherein X 2a -Y 3a -X 3aThe sequence of is selected from the group consisting of: EFQ, EFE, EFN, EFD, NFQ, NFE, NFN, NFD, QFQ, QFE, QFN, QFD, DFQ, DFE, DFN, DFD, EWQ, EWE, EWN, EWD, NWQ, NWE, NWN, NWD, QWQ, QWE, QWN, QWD, DWQ, DWE, DWN, DWD, EYQ, EYE, EFN, EY D, NYQ, NYE, NYN, NYD, QYQ, QYE, QYN, QYD, DYQ, DYE, DYN, DYD, ELQ, ELE, ELN, ELD, NLQ, NLE, NLN , NLD, QLQ, QLE, QLN, QLD, DLQ, DLE, DLN, DLD, RFR, RFQ, RFE, RFN, RFD, RWR, RWQ, RWE, RWN, and RWD.

[0471] 31. The anti-inflammatory composition of embodiment 25, wherein the band-like affinity region comprises sequences selected from the group consisting of, substantially consisting of, or consisting of, the following sequences: RP394, RP108-RP123, RP125-RP131, RP133, RP135-RP141, RP143-RP146, RP148-RP150, RP152-RP165, RP179, RP395, RP211, RP230, RP232, RP258, RP267, RP268, RP271, and RP273 (SEQ ID NO: 33-95, respectively).

[0472] 32. The anti-inflammatory composition of embodiment 25, wherein the band-like affinity region comprises a sequence selected from the group consisting of, substantially consisting of, or consisting of, the following sequences: RP113 (SEQ ID NO:39), RP118 (SEQ ID NO:44), and RP394 (SEQ ID NO:33).

[0473] 33. The anti-inflammatory composition according to any one of embodiments 1 to 13, wherein the band-like affinity region comprises a sequence selected from the group of sequences defined by formula VII: Y 1a -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a (Formula VII)

[0474] 34. The anti-inflammatory composition as described in embodiment 33, wherein Y 2aChoose from the following groups: Phe(F), Trp(W), and Tyr(Y).

[0475] 35. The anti-inflammatory composition as described in embodiment 33, wherein Y 2a Choose from the following groups: Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

[0476] 36. The anti-inflammatory composition as described in any one of embodiments 33 to 35, wherein Y 2b Choose from the following groups: Phe(F), Trp(W), and Tyr(Y).

[0477] 37. The anti-inflammatory composition as described in any one of embodiments 33 to 35, wherein Y 2b Choose from the following groups: Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

[0478] 38. The anti-inflammatory composition according to any one of embodiments 33 to 37, wherein X 1b Choose from the following groups: Arg(R), Lys(K), and His(H).

[0479] 39. The anti-inflammatory composition according to any one of embodiments 33 to 37, wherein X 1b Choose from the following groups: Asn(N), Gln(Q), Asp(D), and Glu(E).

[0480] 40. The anti-inflammatory composition as described in any one of embodiments 33 to 39, wherein X 2a Choose from the following groups: Arg(R), Lys(K), and His(H).

[0481] 41. The anti-inflammatory composition as described in any one of embodiments 33 to 39, wherein X 2a Choose from the following groups: Asn(N), Gln(Q), Asp(D), and Glu(E).

[0482] 42. The anti-inflammatory composition as described in embodiment 33, wherein the sequence X 1b -Y 2a -Y 2b -X 2aChoose from the following groups: Lys-Phe-Phe-Lys (KFFK), Lys-Trp-Trp-Lys (KWWK), Lys-Tyr-Try-Lys (KYYK), Lys-Phe-Trp-Lys (KFWK), Lys-Trp-Phe-Lys (KWFK), Lys-Phe-Tyr-Lys (KFYK), Lys-Tyr-Phe-Lys (KYFK), Lys-Trp-Tyr-Lys (KWYK), and Lys-Tyr-Trp-Lys (KYWK).

[0483] 43. The anti-inflammatory composition as described in embodiment 33, wherein the sequence X 1b -Y 2a -Y 2b -X 2a Choose from the following groups: Arg-Phe-Phe-Arg (RFFR), Arg-Trp-Trp-Arg (RWWR), Arg-Tyr-Try-Arg (RYYR), Arg-Phe-Trp-Arg (RFWR), Arg-Trp-Phe-Arg (RWFR), Arg-Phe-Tyr-Arg (RFYR), Arg-Tyr-Phe-Arg (RYFR), Arg-Trp-Tyr-Arg (RWYR), and Arg-Tyr-Trp-Arg (RYWR).

[0484] 44. The anti-inflammatory composition as described in embodiment 33, wherein the sequence X 1b -Y 2a -Y 2b -X 2a Choose from the following groups: His-Phe-Phe-His (HFFH), His-Trp-Trp-His (HWWH), His-Tyr-Try-His (HYYH), His-Phe-Trp-His (HFWH), His-Trp-Phe-His (HWFH), His-Phe-Tyr-His (HFYH), His-Tyr-Phe-His (HYFH), His-Trp-Tyr-His (HWYH), and His-Tyr-Trp-His (HYWH).

[0485] 45. The anti-inflammatory composition as described in any one of embodiments 33 to 44, wherein X 1a Choose from the following groups: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0486] 46. ​​The anti-inflammatory composition as described in any one of embodiments 33 to 44, wherein X 1a Choose from the following groups: Arg(R) and Gln(Q).

[0487] 47. The anti-inflammatory composition as described in any one of embodiments 33 to 46, wherein X 2b Choose from the following groups: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0488] 48. The anti-inflammatory composition as described in any one of embodiments 33 to 46, wherein X 2b Choose from the following groups: Arg(R) and Gln(Q).

[0489] 49. The anti-inflammatory composition as described in any one of embodiments 33 to 48, wherein Y 1a Choose from the following groups: Phe(F), Trp(W), and Tyr(Y).

[0490] 50. The anti-inflammatory composition as described in any one of embodiments 33 to 48, wherein Y 1a Choose from the following groups: Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

[0491] 51. The anti-inflammatory composition according to any one of embodiments 33 to 50, wherein Y 3a Choose from the following groups: Phe(F), Trp(W), and Tyr(Y).

[0492] 52. The anti-inflammatory composition as described in any one of embodiments 33 to 50, wherein Y 3a Choose from the following groups: Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

[0493] 53. The anti-inflammatory composition of embodiment 33, wherein the band-like affinity region comprises a sequence selected from the group consisting of: FX 1a -X 1b -FF-X 2a -X 2b -F(SEQ ID NO:9), FX 1a -X 1b -FF-X 2a -X 2b -W(SEQ IDNO:10), WX 1a -X1b -FF-X 2a -X 2b -F(SEQ ID NO:11)、F-X 1a -X 1b -FW-X 2a -X 2b -F(SEQ ID NO:12)、F-X 1a -X 1b -WF-X 2a -X 2b -F(SEQ ID NO:13)、F-X 1a -X 1b -WW-X 2a -X 2b -F(SEQ ID NO:14)、W-X 1a -X 1b -WW-X 2a -X 2b -F(SEQ ID NO:15)、F-X 1a -X 1b -WW-X 2a -X 2b -W(SEQ ID NO:16)、W-X 1a -X 1b -WW-X 2a -X 2b -W(SEQ ID NO:17)、F-X 1a -X 1b -FF-X 2a -X 2b -Y(SEQ ID NO:18)、Y-X 1a -X 1b -FF-X 2a -X 2b -F(SEQID NO:19)、F-X 1a -X 1b -FY-X 2a -X 2b -F(SEQ ID NO:20)、F-X 1a -X 1b -YF-X 2a -X 2b -F(SEQ ID NO:21)、F-X 1a -X 1b -YY-X 2a -X 2b -F(SEQ ID NO:22)、Y-X 1a -X 1b -YY-X 2a-X 2b -F(SEQ ID NO:23), FX 1a -X 1b -YY-X 2a -X 2b -Y (SEQ ID NO:24) and YX 1a -X 1b -YY-X 2a -X 2b -Y(SEQ ID NO:25), YX 1a -X 1b -YY-X 2a -X 2b -W(SEQ ID NO:26), WX 1a -X 1b -YY-X 2a -X 2b -Y(SEQ ID NO:27), YX 1a -X 1b -YW-X 2a -X 2b -Y(SEQ ID NO:28), YX 1a -X 1b -WY-X 2a -X 2b -Y(SEQ ID NO:29), YX 1a -X 1b -WW-X 2a -X 2b -Y(SEQ ID NO:30), WX 1a -X 1b -WW-X 2a -X 2b -Y (SEQ ID NO:31) and YX 1a -X 1b -WW-X 2a -X 2b -W(SEQID NO:32).

[0494] 54. The anti-inflammatory composition as described in embodiment 53, wherein X 1a X 1b X 2a and X 2b Each of the following groups is selected independently: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0495] 55. The anti-inflammatory composition as described in embodiment 53 or 54, wherein X 1b and X2a Each of them independently chooses from the following groups: Arg(R), Lys(K), and His(H).

[0496] 56. The anti-inflammatory composition according to any one of embodiments 33 to 55, wherein the band-like affinity region comprises Y directly bound to formula VII. 1a The first additional amino acid residue, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

[0497] 57. The anti-inflammatory composition as described in embodiment 56, wherein the first additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and Tyr (Y).

[0498] 58. The anti-inflammatory composition according to any one of embodiments 33 to 55, wherein the band-like affinity region comprises Y directly bound to formula VII. 3a The first additional amino acid residue, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

[0499] 59. The anti-inflammatory composition as described in embodiment 58, wherein the first additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and Tyr (Y).

[0500] 60. The anti-inflammatory composition according to any one of embodiments 33 to 55, wherein the band-like affinity region comprises Y directly bound to formula VII. 1a The first additional amino acid residue, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

[0501] 61. The anti-inflammatory composition as described in embodiment 60, wherein the first additional amino acid residue is selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0502] 62. The anti-inflammatory composition according to any one of embodiments 33 to 55, wherein the band-like affinity region comprises Y directly bound to formula VII. 3a The first additional amino acid residue, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

[0503] 63. The anti-inflammatory composition as described in embodiment 62, wherein the first additional amino acid residue is selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0504] 64. The anti-inflammatory composition according to any one of embodiments 56, 57, 60 or 61, wherein the band-like affinity region comprises Y directly bound to formula VII. 3a The second additional amino acid residue, wherein the second additional amino acid residue is a hydrophobic amino acid residue.

[0505] 65. The anti-inflammatory composition as described in embodiment 64, wherein the second additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and Tyr (Y).

[0506] 66. The anti-inflammatory composition as described in any one of embodiments 58, 59, 62, or 63, wherein the band-like affinity region comprises Y directly bound to formula VII. 1a The second additional amino acid residue, wherein the second additional amino acid residue is a hydrophilic amino acid residue.

[0507] 67. The anti-inflammatory composition as described in embodiment 66, wherein the second additional amino acid residue is selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0508] 68. The anti-inflammatory composition of embodiment 33, wherein the band-like affinity region comprises a sequence selected from the group consisting of, substantially consisting of, or consisting of, the following sequences: RP124, RP132, RP134, RP142, RP147, RP151, RP166-RP172, RP175, RP177, RP182, RP183, RP185, RP186, RP424, RP190, RP194, RP198, RP199-RP202, RP204, RP206, RP207, RP209, RP210, RP212-RP216, RP218, RP219, RP425, RP225, RP227, RP233-RP239, RP398, RP241-RP247, RP250-RP256, and RP426 (SEQ ID NO. 1, 1, 1, 2, 2, 3, 4, 5, 6, 7, 8, 9, 1, 1, 2 ... NO:106-170).

[0509] 69. The anti-inflammatory composition of embodiment 33, wherein the band-like affinity region comprises a sequence selected from the group consisting of, substantially consisting of, or consisting of, the following sequences: RP124 (SEQ ID NO: 106), RP166 (SEQ ID NO: 112), RP182 (SEQ ID NO: 121), and RP183 (SEQ ID NO: 122).

[0510] 70. The anti-inflammatory composition according to any one of embodiments 1 to 15, wherein the band-like affinity region comprises a sequence selected from the group defined by any one of formulas I-XLVIII and L: Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula I); Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c -X 2a -Y 3a -X 3a (Formula II); X 2a -Y 3a -X 3a -Y 1a -Y 1b -Y 1c -X 1a -Y 2a -Y 2b -Y 2c (Formula III); X 1a -X 1b -X 1c -Y 2a -X 2a -X 2b -X 2c (Form IV); Y 1a -X 1a -X 1b -X 1c -Y 2a -X 2a -X 2b -X 2c -Y 3a -X 3a (Formula V); X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b (Form VI); Y 1a -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a (Equation VII); Y1a -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a -Y 3b -X 3a (Formula VIII); Y 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a -Y 3b (Formula IX); Y 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -Y 3a -X 3a (Formula X); X 1a -Y 1a -X 2a -X 2b -Y 2a -Y 2b -X 3a -X 3b -Y 3a -Y 3b (Formula XI); X 1a -Y 1a -Y 1b -X 2a -X 2b -Y 2a -Y 2b -X 3a -X 3b -Y 3a (Formula XII); Y 1a -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -X 2c -Y 3a -Y 3b (Formula XIII); X 1a -X 1b -X 1c -Y 1a -Y1b -X 2a -X 2b -Y 2a -Y 2b -Y 2c (Formula XIV); Y 1a -Y 1b -Y 1c -X 1a -X 1b -Y 2a -Y 2b -X 2a -X 2b -X 2c (Formula XV); Y 1a -Y 1b -X 1a -X 1b -X 1c -Y 2a -Y 2b -X 2a -X 2b -Y 3a (Formula XVI); Y 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b (Formula XVII); X 1a -Y 1a -Y 1b -X 2a -X 2b -Y 2a -Y 2b -X 3a (Formula XVIII); Y 1a -Y 1b -X 1a -X 1b -Y 2a -Y 2b -X 2a -Y 3a -Y 3b -X 3a (Formula XIX); X 1a -Y 1a -Y 1b -X 2a -Y 2a -Y 2b -X 3a -X 3b -Y 3a -Y 3b (Formula XX); Y 1a -Y 1b -X 1a -X 1b -Y2a -X 2a -X 2b -Y 3a -Y 3b (Formula XXI); X 1a -Y 1a -Y 1b -X 2a -X 2b -X 2c -Y 2a -X 3a -Y 3a -Y 3b (Formula XXII); Y 1a -Y 1b -X 1a -Y 2a -X 2a -X 2b -X 2c -Y 3a -Y 3b -X 3a (Formula XXIII); X 1a -X 1b -Y 1a -X 2a -Y 2a -X 3a -X 3b (Formula XXIV); Y 1a -Y 1b -Y 1c -X 1a -X 1b -Y 2a -X 2a -Y 3a -X 3a -X 3b (Formula XXV); X 1a -X 1b -Y 1a -X 2a -Y 2a -X 3a -X 3b -Y 3a -Y 3b -Y 3c (Formula XXVI); X 1a -X 1b -X 1c -Y 1a -Y 1b -Y 1c (Formula XXVII); X 1a -X 1b -X 1c -X 1d -Y 1a -Y1b -Y 1c -Y 1d (Formula XXVIII); Y 1a -X 1a -X 1b -X 1c -X 1d -Y 2a -Y 2b -Y 2c -Y 2d -X 2a (Formula XXIX); X 1a -X 1b -X 1c -X 1d -X 1e -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e (Formula XXX); Y 1a -Y 1b -X 1a -X 1b -X 1c -Y 2a -Y 2b -Y 2c -X 2a -X 2b (Formula XXXI); X 1a -Y 1a -X 2a -Y 2a -X 3a -X 3b -X 3c -Y 3a -Y 3b -Y 3c (Formula XXXII); Y 1a -Y 1b -Y 1c -X 1a -X 1b -X 1c (Formula XXXIII); Y 1a -Y 1b -Y 1c -Y 1d -X 1a -X 1b -X 1c -X 1d (Formula XXXIV); X 1a -Y 1a -Y 1b -Y 1c -Y 1d -X 2a -X2b -X 2c -X 2d -Y 2a (Formula XXXV); Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 1a -X 1b -X 1c -X 1d -X 1e (Formula XXXVI); X 1a -X 1b -Y 1a -Y 1b -Y 1c -X 2a -X 2b -X 2c -Y 2a -Y 2b (Formula XXXVII); Y 1a -Y 1b -Y 1c -X 1a -X 1a -X 1c -Y 2a -X 2a -Y 3a -X 3a (Formula XXXVIII); Y 1a -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a (Formula XXXIX); Y 1a -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a -Y 2b -Y 2c -Y 2d (Formula XL); Y 1a -Y 1b -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a -Y 2b -Y 2c (Formula XLI); Y 1a -Y 1b -Y1c -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a -Y 2b (Formula XLII); Y 1a -Y 1b -Y 1c -Y 1e -X 1a -X 1b -X 1c -X 1d -X 1e -Y 2a (Formula XLIII); X 1a -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a (Formula XLIV); X 1a -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a -X 2b -X 2c -X 2d (Formula XLV); X 1a -X 1b -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a -X 2b -X 2c (Formula XLVI); X 1a -X 1b -X 1c -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X 2a -X 2b (Formula XLVII); X 1a -X 1b -X 1c -X 1d -Y 1a -Y 1b -Y 1c -Y 1d -Y 1e -X2a (Formula XLVIII); and Y 1a -Y 1b -X 1a -Y 2a -Y 2b -X 2a -Y 3a -Y 3b -X 3a -Y 4a (Formula L).

[0511] 71. The anti-inflammatory composition as described in embodiment 70, wherein Y 1a Y 1b Y 1c Y 2a Y 2b Y 2c Y 3a Y 3b and Y 3c Each of the following groups is selected individually: Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

[0512] 72. The anti-inflammatory composition as described in embodiment 70, wherein Y 1a Y 1b Y 1c Y 2a Y 2b Y 2c Y 3a Y 3b and Y 3c Each of them individually selects from the following groups: Phe(F), Trp(W), and Tyr(Y).

[0513] 73. The anti-inflammatory composition according to any one of embodiments 70 to 72, wherein X 1a X 1b X 1c X 2a X 2b X 2c X 3a and X 3b Each of the following groups is selected individually: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0514] 74. The anti-inflammatory composition as described in any one of embodiments 70 to 73, wherein X 1a X 1b X 1c X2a X 2b X 2c X 3a and X 3b Each of them individually selects from the following groups: Arg(R), Lys(K), His(H), and Gln(Q).

[0515] 75. The anti-inflammatory composition according to any one of embodiments 70 to 74, wherein the banded affinity region comprises a first additional amino acid residue directly bound to the N-terminus of any one of formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

[0516] 76. The anti-inflammatory composition of embodiment 70, wherein the first additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and Tyr (Y).

[0517] 77. The anti-inflammatory composition according to any one of embodiments 70 to 74, wherein the banded affinity region comprises a first additional amino acid residue that is directly bound to the C-terminus of any one of formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

[0518] 78. The anti-inflammatory composition as described in embodiment 77, wherein the first additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and Tyr (Y).

[0519] 79. The anti-inflammatory composition according to any one of embodiments 70 to 74, wherein the banded affinity region comprises a first additional amino acid residue that binds directly to the N-terminus of any one of formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

[0520] 80. The anti-inflammatory composition as described in embodiment 79, wherein the first additional amino acid residue is selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0521] 81. The anti-inflammatory composition according to any one of embodiments 70 to 74, wherein the banded affinity region comprises a first additional amino acid residue directly bound to the C-terminus of any one of formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

[0522] 82. The anti-inflammatory composition as described in embodiment 81, wherein the first additional amino acid residue is selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0523] 83. The anti-inflammatory composition according to any one of embodiments 75, 76, 79 or 80, wherein the banded affinity region comprises a second additional amino acid residue directly bound to the C-terminus of any one of formulas I-XLVIII and L, wherein the second additional amino acid residue is a hydrophobic amino acid residue.

[0524] 84. The anti-inflammatory composition of embodiment 83, wherein the second additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and Tyr (Y).

[0525] 85. The anti-inflammatory composition according to any one of embodiments 77, 78, 81 or 82, wherein the banded affinity region comprises a second additional amino acid residue directly bound to the N-terminus of any one of formulas I-XLVIII and L, wherein the second additional amino acid residue is a hydrophilic amino acid residue.

[0526] 86. The anti-inflammatory composition of embodiment 81, wherein the second additional amino acid residue is selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0527] 87. The anti-inflammatory composition of embodiment 70, wherein the band-like affinity region comprises a sequence selected from the group consisting of, substantially consisting of, or consisting of, the following sequences: RP396, RP405, RP174, RP176, RP178, RP180-181, RP184, RP408, RP187, RP416, RP188, RP189, RP388, RP417, RP191-RP193, RP404, RP196, RP397, RP197, RP402, RP203, RP40 9. RP205, RP208, RP217, RP220-RP224, RP226, RP229, RP231, RP240, RP248, RP249, RP415, RP257, RP259-RP266, RP269, RP272, RP406, RP422, RP407, RP400, RP419, RP401, RP423, RP411, RP418, RP428, RP420, RP421, RP429, RP413, RP430, RP270 (SEQ ID NO: 174-224 and 234-249 respectively).

[0528] 88. The anti-inflammatory composition as described in any one of embodiments 1 to 9 or 15, wherein the band-like affinity region comprises a sequence selected from the group of sequences defined by formula XLIX:

[0529] Y 1a -X 1a -Y 2a -X 2a -Y 3a -X 3a (Formula XLIX).

[0530] 89. The anti-inflammatory composition as described in embodiment 88, wherein Y 1a Y 2a and Y 3a Each of the following groups is independently selected: Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), and Met (M).

[0531] 90. The anti-inflammatory composition as described in embodiment 88, wherein Y 1a Y 2a and Y 3a Each of them independently chooses from the following groups: Phe(F), Trp(W), and Tyr(Y).

[0532] 91. The anti-inflammatory composition according to any one of embodiments 88 to 90, wherein X 1aX 2a and X 3a Each of the following groups is selected independently: Arg(R), Lys(K), His(H), Gln(Q), Glu(E), Asn(N), and Asp(D).

[0533] 92. The anti-inflammatory composition as described in any one of embodiments 88 to 90, wherein X 1a X 2a and X 3a Each of them independently chooses from the following groups: Arg(R), Lys(K), and His(H).

[0534] 93. The anti-inflammatory composition according to any one of embodiments 88 to 92, wherein the band-like affinity region comprises Y directly bound to formula XLIX. 1a The first additional amino acid residue, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

[0535] 94. The anti-inflammatory composition as described in embodiment 93, wherein the first additional amino acid residue is selected from the group consisting of: Arg(R), Lys(K), His(H), Asn(N), Gln(Q), Asp(D), and Glu(E).

[0536] 95. The anti-inflammatory composition as described in embodiment 93, wherein the first additional amino acid residue is selected from the group consisting of Arg(R), Lys(K) and His(H).

[0537] 96. The anti-inflammatory composition according to any one of embodiments 88 to 92, wherein the band-like affinity region comprises X directly bound to formula XLIX. 3a The first additional amino acid residue, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

[0538] 97. The anti-inflammatory composition as described in embodiment 96, wherein the first additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W), (Tyr), Leu (L), Ile (I), Cys (C), and Met (M).

[0539] 98. The anti-inflammatory composition as described in embodiment 96, wherein the first additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and (Tyr).

[0540] 99. The anti-inflammatory composition according to any one of embodiments 93 to 95, wherein the band-like affinity region comprises X directly bound to formula XLIX. 3aThe second additional amino acid residue, wherein the second additional amino acid residue is a hydrophobic amino acid residue.

[0541] 100. The anti-inflammatory composition as described in embodiment 99, wherein the second additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W), (Tyr), Leu (L), Ile (I), Cys (C), and Met (M).

[0542] 101. The anti-inflammatory composition as described in embodiment 99, wherein the second additional amino acid residue is selected from the group consisting of: Phe (F), Trp (W) and Tyr (Y).

[0543] 102. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acid residues in length and contains a banded affinity region having at least 70% identity with the sequence NFNFFFRFFF (RP394, SEQ ID NO:33), wherein the peptide binds to a dimerizing site on an NFkB class II protein.

[0544] 103. The anti-inflammatory composition as described in embodiment 102, wherein the peptide is further bound to human serum albumin.

[0545] 104. The anti-inflammatory composition as described in embodiment 102 or 103, wherein the difference between the banded affinity region of the peptide and the sequence NFNFFFRFFF (SEQ ID NO:33) is limited to conserved or highly conserved amino acid substitutions.

[0546] 105. The anti-inflammatory composition as described in embodiment 102 or 103, wherein the band affinity region of the peptide differs from the sequence NFNFFFRFFF (SEQ ID NO:33) by replacing one or more phenylalanine (F) residues with amino acid residues selected from the group consisting of: Trp (W), Tyr (Y), His (H), and Leu (L).

[0547] 106. The anti-inflammatory composition as described in embodiment 102 or 103, wherein the band-like affinity region of the peptide differs from the sequence NFNFFFRFFF (SEQ ID NO:33) by the absence of one, two, or three amino acids.

[0548] 107. The anti-inflammatory composition of embodiment 106, wherein the missing amino acid is located at the N-terminus, C-terminus, or both ends of the sequence NFNFFFRFFF (SEQ ID NO:33).

[0549] 108. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acid residues in length and comprises a banded affinity region having at least 70% identity with the sequence FFFRFFFNFN (RP118, SEQ ID NO:44), wherein the peptide binds to a dimerizing site on an NFkB class II protein.

[0550] 109. The anti-inflammatory composition as described in embodiment 108, wherein the peptide is further bound to human serum albumin.

[0551] 110. The anti-inflammatory composition as described in embodiment 108 or 109, wherein the difference between the banded affinity region of the peptide and the sequence FFFRFFFNFN (SEQ ID NO:44) is limited to conserved or highly conserved amino acid substitutions.

[0552] 111. The anti-inflammatory composition as described in embodiment 108 or 109, wherein the banding affinity region of the peptide differs from the sequence FFFRFFFNFN (SEQ ID NO:44) by replacing one or more phenylalanine (F) residues with amino acid residues selected from the group consisting of: Trp (W), Tyr (Y), His (H), and Leu (L).

[0553] 112. The anti-inflammatory composition as described in embodiment 108 or 109, wherein the band-like affinity region of the peptide differs from the sequence FFFRFFFNFN (SEQ ID NO:44) by the deletion of one, two, or three amino acids.

[0554] 113. The anti-inflammatory composition as described in embodiment 112, wherein the missing amino acid is located at the N-terminus, C-terminus, or both ends of the sequence FFFRFFFNFN (SEQ ID NO:44).

[0555] 114. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acid residues in length and contains a banded affinity region having at least 70% identity with the sequence FFRKFAKRFK (RP183, SEQ ID NO: 122), wherein the peptide binds to a dimerizing site on an NFkB class II protein.

[0556] 115. The anti-inflammatory composition as described in embodiment 114, wherein the peptide is further bound to human serum albumin.

[0557] 116. The anti-inflammatory composition as described in embodiment 114 or 115, wherein the difference between the banded affinity region of the peptide and the sequence FFRKFAKRFK (SEQ ID NO: 122) is limited to conserved or highly conserved amino acid substitutions.

[0558] 117. The anti-inflammatory composition as described in embodiment 114 or 115, wherein the banded affinity region of the peptide differs from the sequence FFRKFAKRFK (SEQ ID NO: 122) by replacing one or more phenylalanine (F) residues with amino acid residues selected from the group consisting of: Trp (W), Tyr (Y), and Leu (L).

[0559] 118. The anti-inflammatory composition as described in embodiment 114 or 115, wherein the banded affinity region of the peptide differs from the sequence FFRKFAKRFK (SEQ ID NO: 122) by the deletion of one, two, or three amino acids.

[0560] 119. The anti-inflammatory composition of embodiment 118, wherein the missing amino acid is located at the N-terminus, C-terminus, or both ends of the sequence FFRKFAKRFK (SEQ ID NO: 122).

[0561] 120. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acid residues in length and contains a banded affinity region having at least 70% identity with the sequence KFRKAFKRFF (RP182, SEQ ID NO: 121), wherein the peptide binds to a dimerizing site on an NFkB class II protein.

[0562] 121. The anti-inflammatory composition as described in embodiment 120, wherein the peptide is further bound to human serum albumin.

[0563] 122. The anti-inflammatory composition as described in embodiment 120 or 121, wherein the difference between the banded affinity region of the peptide and the sequence KFRKAFKRFF (SEQ ID NO: 121) is limited to conserved or highly conserved amino acid substitutions.

[0564] 123. The anti-inflammatory composition of embodiment 120 or 121, wherein the banded affinity region of the peptide differs from the sequence KFRKAFKRFF (SEQ ID NO: 121) by replacing one or more phenylalanine (F) residues with amino acid residues selected from the group consisting of: Trp (W), Tyr (Y), and Leu (L).

[0565] 124. The anti-inflammatory composition as described in embodiment 120 or 121, wherein the band-like affinity region of the peptide differs from the sequence KFRKAFKRFF (SEQ ID NO: 121) by the deletion of one, two, or three amino acids.

[0566] 125. The anti-inflammatory composition of embodiment 124, wherein the missing amino acid is located at the N-terminus, C-terminus, or both ends of the sequence KFRKAFKRFF (SEQ ID NO: 121).

[0567] 126. The anti-inflammatory composition according to any one of embodiments 1 to 125, wherein the peptide binds to the dimer site on Rel B (SEQ ID NO:367) with a binding energy of at least -650 kcal / mol.

[0568] 127. The anti-inflammatory composition according to any one of embodiments 1 to 126, wherein the peptide binds to a dimer site on Rel B (SEQ ID NO: 367) and directly contacts at least one amino acid residue of Rel B selected from the group consisting of: Glu 298, Tyr-300, Leu-301, Leu-302, Asp-330, His-332, and Leu-371.

[0569] 128. The anti-inflammatory composition of embodiment 127, wherein the peptide forms an ionic bond with Asp-330, an ionic bond with His-332, and / or a hydrophobic contact with Leu-371 when it binds to a dimerizing site on Rel B.

[0570] 129. The anti-inflammatory composition according to any one of embodiments 1 to 128, wherein the peptide binds to at least one signaling molecule selected from the group consisting of: TGFβ (SEQ ID NO:368), Notch1 (SEQ ID NO:369), Wnt8R (SEQ ID NO:370), TRAIL (SEQ ID NO:371), IL6R (SEQ ID NO:372), IL10R (SEQ ID NO:373), EGFR (SEQ ID NO:374), CDK6 (SEQ ID NO:375), histone methyltransferase (HMT) (SEQ ID NO:376), CD47 (SEQ ID NO:377), SIRP-α (SEQ ID NO:378), CD206 (SEQ ID NO:379), TGM2 (SEQ ID NO:380); LEGUMAIN (SEQ ID NO:413), CD209 (SEQ ID NO:414), FAS (SEQ ID NO:415), PD-1 (SEQ ID NO:380); LEGUMAIN (SEQ ID NO:413), CD209 (SEQ ID NO:414), FAS (SEQ ID NO:415), PD-1 (SEQ ID NO:380). NO:416), MKK7 (SEQ ID NO:417), and RNR (SEQ ID NO:418).

[0571] 130. The anti-inflammatory composition of embodiment 129, wherein the peptide binds to TGFβ (SEQ ID NO:368) with a binding energy of at least -650 kcal / mol.

[0572] 131. The anti-inflammatory composition as described in embodiment 129 or 130, wherein the peptide binds to TGFβ (SEQ ID NO: 368) and directly contacts at least one amino acid residue of TGFβ selected from the group consisting of: Leu-20, Ile-22, Phe-24, Asp-27, Leu-28, Trp-30, Trp-32, Tyr-39, Phe-43, Pro-80, Leu-83, Leu-101, and Ser-112.

[0573] 132. The anti-inflammatory composition according to any one of embodiments 129 to 131, wherein the peptide binds to Notch1 (SEQ ID NO:369) with a binding energy of at least -650 kcal / mol.

[0574] 133. The anti-inflammatory composition according to any one of embodiments 120 to 123, wherein the peptide binds to Notch (SEQ ID NO: 369) and directly contacts at least one amino acid residue of Notch selected from the group consisting of: Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala-1553, Glu-1556, Trp-1557, Cys-1562, His-1602, Arg-1684, Gln-1685, Cys-1686, Ser-1691, Cys-1693, Phe-1694, and Phe-1703.

[0575] 134. The anti-inflammatory composition according to any one of embodiments 129 to 133, wherein the peptide binds to Wnt8R (SEQ ID NO:370) with a binding energy of at least -600 kcal / mol.

[0576] 135. The anti-inflammatory composition according to any one of embodiments 129 to 134, wherein the peptide binds to Wnt8R (SEQ ID NO: 370) and directly contacts at least one amino acid residue of Wnt8R selected from the group consisting of: Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr-100, Lys-101, Pro-103, Pro-105, Pro-106, Arg-137, and Asp-145.

[0577] 136. The anti-inflammatory composition according to any one of embodiments 129 to 135, wherein the peptide binds to TRAIL (SEQ ID NO:371) with a binding energy of at least -650 kcal / mol.

[0578] 137. The anti-inflammatory composition according to any one of embodiments 120 to 127, wherein the peptide binds to TRAIL (SEQ ID NO: 371) and directly contacts at least one amino acid residue of TRAIL selected from the group consisting of: Arg-130, Arg-158, Ser-159, Gly-160, His-161, Phe-163, Tyr-189, Arg-189, Gln-193, Glu-195, Glu-236, Tyr-237, Leu-239, Asp-267, Asp-269, His-270, and Glu-271.

[0579] 138. The anti-inflammatory composition according to any one of embodiments 129 to 137, wherein the peptide binds to IL6R (SEQ ID NO:372) with a binding energy of at least -600 kcal / mol.

[0580] 139. The anti-inflammatory composition according to any one of embodiments 129 to 138, wherein the peptide binds to IL6R (SEQ ID NO:372) and directly contacts at least one amino acid residue of IL6R selected from the group consisting of: Glu-163, Gly-164, Phe-168, Gln-190, Phe-229, Tyr-230, Phe-279, and Gln-281.

[0581] 140. The anti-inflammatory composition according to any one of embodiments 129 to 139, wherein the peptide binds to IL10R (SEQ ID NO:373) with a binding energy of at least -600 kcal / mol.

[0582] 141. The anti-inflammatory composition according to any one of embodiments 129 to 140, wherein the peptide binds to IL10R (SEQ ID NO:373) and directly contacts at least one amino acid residue of IL10R selected from the group consisting of: Tyr-43, Ile-45, Glu-46, Asp-61, Asn-73, Arg-76, Asn-94, Arg-96, Phe-143, Ala-189, Ser-190, and Ser-191.

[0583] 142. The anti-inflammatory composition according to any one of embodiments 129 to 141, wherein the peptide binds to EGFR (SEQ ID NO:374) with a binding energy of at least -650 kcal / mol.

[0584] 143. The anti-inflammatory composition according to any one of embodiments 129 to 142, wherein the peptide binds to EGFR (SEQ ID NO:374) and directly contacts at least one amino acid residue of EGFR selected from the group consisting of: Leu-10, Thr-40, Trp-41, Leu-63, His-66, Asp-68, Leu-88, Tyr-101, Asp-48, and Phe-51.

[0585] 144. The anti-inflammatory composition according to any one of embodiments 129 to 143, wherein the peptide binds to CDK6 (SEQ ID NO:375) with a binding energy of at least -600 kcal / mol.

[0586] 145. The anti-inflammatory composition according to any one of embodiments 129 to 144, wherein the peptide binds to CDK6 (SEQ ID NO: 375) and directly contacts at least one amino acid residue of CDK6 selected from the group consisting of: Val-142, Arg-144, Asp-145, Ser-171, Val-180, Val-181, Leu-183, Arg-186, Val-190, Gln-193, Tyr-196, and Val-200.

[0587] 146. The anti-inflammatory composition according to any one of embodiments 129 to 145, wherein the peptide binds to histone methyltransferase (HMT) (SEQ ID NO:376) with a binding energy of at least -600 kcal / mol.

[0588] 147. The anti-inflammatory composition according to any one of embodiments 129 to 146, wherein the peptide binds to HMT (SEQ ID NO:376) and directly contacts at least one amino acid residue of HMT selected from the group consisting of: Asn-69, His-70, Ser-71, Lys-72, Asp-73, Pro-74, and Asn-75.

[0589] 148. The anti-inflammatory composition according to any one of embodiments 129 to 147, wherein the peptide binds to the SIRP-α binding site on CD47 (SEQ ID NO:377) with a binding energy of at least -550 kcal / mol.

[0590] 149. The anti-inflammatory composition according to any one of embodiments 129 to 148, wherein the peptide binds to CD47 (SEQ ID NO: 377) and directly contacts at least one amino acid residue of CD47 selected from the group consisting of: Glu-29, Ala-30, Glu-35, Val-36, Tyr-37, Lys-39, Thr-49, Asp-51, Glu-97, Thr-99, Leu-101, Thr-102, Arp-103, Glu-104, and Glu-106.

[0591] 150. The anti-inflammatory composition according to any one of embodiments 129 to 149, wherein the peptide binds to the CD47 binding site on SIRP-α (SEQ ID NO:378) with a binding energy of at least -600 kcal / mol.

[0592] 151. The anti-inflammatory composition according to any one of embodiments 129 to 150, wherein the peptide binds to SIRP-α (SEQ ID NO: 378) and directly contacts at least one amino acid residue of SIRP-α selected from the group consisting of: Leu-30, Gln-37, Gln-52, Lys-53, Ser-66, Thr-67, Arg-69, Met-72, Phe-74, Lys-96, and Asp-100.

[0593] 152. The anti-inflammatory composition according to any one of embodiments 129 to 151, wherein the peptide binds to CD206 (SEQ ID NO:379) with a binding energy of at least -650 kcal / mol.

[0594] 153. The anti-inflammatory composition according to any one of embodiments 129 to 152, wherein the peptide binds to CD206 (SEQ ID NO: 379) and directly contacts at least one amino acid residue of CD206 selected from the group consisting of: Glu-725, Tyr-729, Glu-733, Asn-747 and Asp-748.

[0595] 154. The anti-inflammatory composition according to any one of embodiments 129 to 153, wherein the peptide binds to TGM2 (SEQ ID NO:380) with a binding energy of at least -650 kcal / mol.

[0596] 155. The anti-inflammatory composition according to any one of embodiments 129 to 154, wherein the peptide binds to TGM2 (SEQ ID NO: 380) and directly contacts at least one amino acid residue of TGM2 selected from the group consisting of Cys-277, His-335 and Asp-358.

[0597] 156. The anti-inflammatory composition according to any one of embodiments 129 to 155, wherein the peptide binds to LEGUMAIN (SEQ ID NO:413) with a binding energy of at least -600 kcal / mol.

[0598] 157. The anti-inflammatory composition according to any one of embodiments 129 to 156, wherein the peptide binds to LEGUMAIN (SEQ ID NO: 413) and directly contacts at least one amino acid residue of LEGUMAIN selected from the group consisting of: Asn-44, Arg-46, His-159, Glu-189, Cys-191, Ser-217, Ser-218 and Asp-233.

[0599] 158. The anti-inflammatory composition according to any one of embodiments 129 to 157, wherein the peptide binds to CD209 (SEQ ID NO:414) with a binding energy of at least -600 kcal / mol.

[0600] 159. The anti-inflammatory composition according to any one of embodiments 129 to 158, wherein the peptide binds to CD209 (SEQ ID NO: 414) and directly contacts at least one amino acid residue of CD209 selected from the group consisting of: Phe-269, Glu-280, Glu-303, Asn-305, Asn-306, Glu-310, Asp-311, Ser-316, Gly-317, Asn-321, and Lys-324.

[0601] 160. The anti-inflammatory composition according to any one of embodiments 129 to 159, wherein the peptide binds to FAS (SEQ ID NO:415) with a binding energy of at least -600 kcal / mol.

[0602] 161. The anti-inflammatory composition according to any one of embodiments 129 to 160, wherein the peptide binds to FAS (SEQ ID NO: 415) and directly contacts at least one amino acid residue of FAS selected from the group consisting of: Lys-251, Lys-296, Lys-299, Leu-303, Leu-306, Ala-307, Glu-308, Lys-309, Gln-311, Ile-314, Leu-315, Asp-317, Ile-318, and Thr-319.

[0603] 162. The anti-inflammatory composition according to any one of embodiments 129 to 161, wherein the peptide binds to PD-1 (SEQ ID NO:416) with a binding energy of at least -600 kcal / mol.

[0604] 163. The anti-inflammatory composition according to any one of embodiments 129 to 162, wherein the peptide binds to PD-1 (SEQ ID NO:416) and directly contacts at least one amino acid residue of PD-1 selected from the group consisting of: Val-64, Asn-66, Tyr-68, Met-70, Thr-76, Lys-78, Thr-120, Leu-122, Ala-125, and Ser-127.

[0605] 164. The anti-inflammatory composition according to any one of embodiments 129 to 163, wherein the peptide binds to MKK7 (SEQ ID NO:417) with a binding energy of at least -600 kcal / mol.

[0606] 165. The anti-inflammatory composition according to any one of embodiments 129 to 164, wherein the peptide binds to MKK7 (SEQ ID NO:417) and directly contacts at least one amino acid residue of MKK7 selected from the group consisting of: Met-142, Val-150, Lys-152, Lys-165, Met-212, Met-215, Thr-217, Lys-221, Leu-266, Cys-276, and Asp-277.

[0607] 166. The anti-inflammatory composition according to any one of embodiments 129 to 165, wherein the peptide binds to the RNR (SEQ ID NO:418) with a binding energy of at least -600 kcal / mol.

[0608] 167. The anti-inflammatory composition according to any one of embodiments 129 to 166, wherein the peptide binds to an RNR (SEQ ID NO: 418) and directly contacts at least one amino acid residue of an RNR selected from the group consisting of: Asn-426, Leu-427, Cys-428, Glu-430, Met-606, Pro-608, and Ala-610.

[0609] 168. The anti-inflammatory composition according to any one of embodiments 1 to 167, wherein the peptide binds to human serum albumin (HSA) (SEQ ID NO:381) with a binding energy of at least -650 kcal / mol.

[0610] 169. The anti-inflammatory composition according to any one of embodiments 1 to 168, wherein the peptide comprises a banded region of exclusive affinity consisting of D-type amino acid residues.

[0611] 170. The anti-inflammatory composition according to any one of embodiments 1 to 169, wherein the concentration of the peptide in solution is from about 0.1 mg / ml to about 100 mg / ml.

[0612] 171. The anti-inflammatory composition according to any one of embodiments 1 to 170, wherein the composition contains about 1 mg to about 500 mg of the peptide.

[0613] 172. The anti-inflammatory composition as described in embodiment 158 ​​or 171, wherein the composition is substantially free of proteins other than the peptide.

[0614] 173. An anti-inflammatory composition comprising a combination of a first peptide as defined in any one of embodiments 1 to 171 and a second peptide as defined in any one of embodiments 1 to 171, wherein the first peptide and the second peptide may have the same sequence or different sequences.

[0615] 174. The anti-inflammatory composition of embodiment 173, wherein the first peptide and the second peptide are linked together by a peptide bond, a peptide linker, or a non-peptide linker.

[0616] 175. The anti-inflammatory composition of embodiment 173, wherein the first peptide and the second peptide are linked together by a peptide linker, wherein the peptide linker has a sequence selected from the group consisting of: Gly-Gly-Gly (GGG), Gly-Gly-Gly-Arg (GGGR), Gly-Pro-Gly (GPG), and Gly-Pro-Gly-Arg (GPGR).

[0617] 176. The anti-inflammatory composition as described in embodiment 174 or 175, wherein the linked first and second peptides bind to the dimer site on Rel B (SEQ ID NO:367) with a binding energy of at least -700 kcal / mol.

[0618] 177. The anti-inflammatory composition as described in any one of embodiments 1 to 171 and embodiments 173 to 176, further comprising serum albumin.

[0619] 178. The anti-inflammatory composition as described in embodiment 177, wherein the composition is substantially free of blood proteins other than serum albumin.

[0620] 179. A pharmaceutical composition comprising an anti-inflammatory composition as described in any one of embodiments 1 to 178 and a pharmaceutically acceptable carrier.

[0621] 180. The pharmaceutical composition of embodiment 179, wherein the composition comprises a chemotherapeutic agent.

[0622] 181. A method of treating symptoms associated with chronic inflammation, the method comprising administering to a subject suffering from said symptoms a composition according to any one of embodiments 1 to 180.

[0623] 182. The method of embodiment 181, wherein the condition is selected from the group consisting of: irritable bowel disease, ulcerative colitis, colitis, Crohn's disease, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, autoimmune diseases, feline or human immunodeficiency virus (FIV or HIV) infection, and cancer.

[0624] 183. The method as described in embodiment 181 or 182, wherein the subject is a mammal.

[0625] 184. The method as described in any one of embodiments 181 to 183, wherein the subject is a human being.

[0626] 185. The method of any one of embodiments 181 to 184, wherein the anti-inflammatory composition is administered in a dose comprising a peptide between about 1 mg and about 500 mg.

[0627] 186. The method of any one of embodiments 181 to 185, wherein the anti-inflammatory composition is applied intravenously, intraperitoneally, parenterally, in situ, subcutaneously, locally, nasally, via an implantable reservoir, using a nanoparticle-based delivery system, microneedle patch, microsphere, bead, osmotic pump or mechanical pump and / or other mechanical device.

[0628] 187. The method of any one of embodiments 181 to 186, wherein the anti-inflammatory composition is administered in combination with another drug known to be effective in treating the condition.

[0629] 188. The method of embodiment 187, wherein the anti-inflammatory composition is applied before, simultaneously with or after the application of the other drug.

[0630] 189. A method for treating fibrosis in a subject, the method comprising administering to the subject a composition according to any one of embodiments 1 to 180.

[0631] 190. The method of embodiment 189, wherein the fibrosis is selected from the group consisting of: pulmonary fibrosis, skin fibrosis, liver fibrosis, kidney fibrosis, and fibrosis caused by ionizing radiation.

[0632] 191. The method as described in embodiment 189 or 190, wherein the subject is a mammal.

[0633] 192. The method as described in any one of embodiments 189 to 191, wherein the subject is a human being.

[0634] 193. The method of any one of embodiments 189 to 192, wherein the anti-inflammatory composition is administered in a dose comprising a peptide between about 1 mg and about 500 mg.

[0635] 194. The method of any one of embodiments 189 to 193, wherein the anti-inflammatory composition is applied intravenously, intraperitoneally, parenterally, in situ, subcutaneously, locally, nasally, via an implantable reservoir, using a nanoparticle-based delivery system, microneedle patch, microsphere, bead, osmotic pump or mechanical pump and / or other mechanical device.

[0636] 195. The method as described in any one of embodiments 189 to 194, wherein the anti-inflammatory composition is administered in combination with another drug known to be effective in treating fibrosis.

[0637] 196. The method of embodiment 195, wherein the anti-inflammatory composition is applied before, simultaneously with or after the application of the other drug.

[0638] 197. A method for reducing the levels of pro-inflammatory cytokines in a subject suffering from chronic inflammatory symptoms, the method comprising administering to the subject a composition according to any one of embodiments 1 to 180.

[0639] 198. The method of embodiment 197, wherein the chronic inflammatory symptoms are selected from the group consisting of: irritable bowel disease, ulcerative colitis, colitis, Crohn's disease, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, autoimmune diseases, feline or human immunodeficiency virus (FIV or HIV) infection, and cancer.

[0640] 199. The method of embodiment 197 or 198, wherein the method reduces the level of at least one cytokine selected from the group consisting of: NF-κB, TNFα, IL1, IL6, IL12, MMP-1, MMP-9, MCP-1, IL8, IL17, and IL23.

[0641] 200. The method as described in embodiment 199, wherein the level of the at least one cytokine is reduced by at least 10%.

[0642] 201. The method as described in any one of embodiments 197 to 200, wherein the subject is a mammal.

[0643] 202. The method as described in any one of embodiments 197 to 201, wherein the subject is a human being.

[0644] 203. The method of any one of embodiments 197 to 202, wherein the anti-inflammatory composition is administered in a dose comprising a peptide between about 1 mg and about 500 mg.

[0645] 204. The method of any one of embodiments 197 to 203, wherein the anti-inflammatory composition is applied intravenously, intraperitoneally, parenterally, in situ, subcutaneously, locally, nasally, via an implantable reservoir, using a nanoparticle-based delivery system, microneedle patch, microsphere, bead, osmotic pump or mechanical pump and / or other mechanical device.

[0646] 205. The method of any one of embodiments 197 to 204, wherein the anti-inflammatory composition is administered in combination with another drug known to be effective in treating the chronic inflammatory symptoms suffered by the subject.

[0647] 206. The method of embodiment 205, wherein the anti-inflammatory composition is applied before, simultaneously with or after the application of the other drug.

[0648] 207. A method of treating cancer in a subject, the method comprising administering to the subject an anti-inflammatory composition according to any one of embodiments 1 to 180.

[0649] 208. The method of embodiment 207, wherein the cancer is selected from the group consisting of colon cancer and breast cancer.

[0650] 209. The method as described in embodiment 207 or 208, wherein the anti-inflammatory composition is administered in combination with a chemotherapeutic agent or a cell therapy agent.

[0651] 210. The method of embodiment 209, wherein the chemotherapeutic agent or cell therapy agent is selected from the group consisting of: steroids, anthracyclines, thyroid hormone replacement drugs, thymidine acid-targeting drugs, checkpoint inhibitors, chimeric antigen receptor / T-cell therapy agents, and other cell therapy agents.

[0652] 211. The method of embodiment 209, wherein the chemotherapeutic agent is selected from the group consisting of: gemcitabine, docetaxel, bleomycin, erlotinib, gefitinib, lapatinib, imatinib, dasatinib, nilotinib, besutinib, crizotinib, ceritinib, trametinib, bevacizumab, sunitinib, sorafenib, trastuzumab, ado-trastuzumab emtansine, rituximab, ipilimumab, rapamycin, tanciolimus, everolimus, methotrexate, doxorubicin, abraxane, folfirinox, cisplatin, carboplatin, 5-fluorouracil, Teysumo, paclitaxel, dehydrocortisone, levothyroxine, and pemetrexed.

[0653] 212. The method of any one of embodiments 209 to 211, wherein the anti-inflammatory composition is applied before, simultaneously with or after the application of the chemotherapeutic agent or cell therapy agent.

[0654] 213. The method as described in embodiment 207 or 208, wherein the anti-inflammatory composition is administered in combination with radiation therapy.

[0655] 214. The method of embodiment 213, wherein the anti-inflammatory composition is applied before or after the radiation therapy.

[0656] 215. The method as described in any one of embodiments 207 to 214, wherein the subject is a mammal.

[0657] 216. The method as described in any one of embodiments 207 to 215, wherein the subject is a human being.

[0658] 217. The method of any one of embodiments 207 to 216, wherein the anti-inflammatory composition is administered in a dose comprising a peptide between about 1 mg and about 500 mg.

[0659] 218. The method of any one of embodiments 207 to 217, wherein the anti-inflammatory composition is administered intravenously, intraperitoneally, extragastrically, in situ, subcutaneously, nasally, via an implantable reservoir, using a nanoparticle-based delivery system, microneedle patch, microsphere, bead, osmotic pump or mechanical pump and / or other mechanical device. sequence list <110> Turbulent Biosciences Ltd. Jesse M. Johnny Henry W. Lopez George R. Martin Clayton Yates Charles E. Gavin <120> Peptides with anti-inflammatory properties <130> RIPT-001 <140> US 14 / 882,293 <141> 2015-10-13 <150> US 62 / 063,909 <151> 2014-10-14 <160> 418 <170> PatentIn version 3.5 <210> 1 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 1 Phe Phe Phe Xaa Phe Phe Phe 1 5 <210> 2 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 2 Trp Trp Trp Xaa Trp Trp Trp 1 5 <210> 3 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 3 Tyr Tyr Tyr Xaa Tyr Tyr Tyr 1 5 <210> 4 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 4 Leu Leu Leu Xaa Leu Leu Leu 1 5 <210> 5 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 5 Cys Cys Cys Xaa Cys Cys Cys 1 5 <210> 6 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 6 Met Met Met Xaa Met Met Met 1 5 <210> 7 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 7 Val Val Val Xaa Val Val Val 1 5 <210> 8 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (4)..(4) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 8 Ile Ile Ile Xaa Ile Ile Ile 1 5 <210> 9 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 9 Phe Xaa Xaa Phe Phe Xaa Xaa Phe 1 5 <210> 10 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 10 Phe Xaa Xaa Phe Phe Xaa Xaa Trp 1 5 <210> 11 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 11 Trp Xaa Xaa Phe Phe Xaa Xaa Phe 1 5 <210> 12 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 12 Phe Xaa Xaa Phe Trp Xaa Xaa Phe 1 5 <210> 13 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 13 Phe Xaa Xaa Trp Phe Xaa Xaa Phe 1 5 <210> 14 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 14 Phe Xaa Xaa Trp Trp Xaa Xaa Phe 1 5 <210> 15 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 15 Trp Xaa Xaa Trp Trp Xaa Xaa Phe 1 5 <210> 16 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 16 Phe Xaa Xaa Trp Trp Xaa Xaa Trp 1 5 <210> 17 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 17 Trp Xaa Xaa Trp Trp Xaa Xaa Trp 1 5 <210> 18 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 18 Phe Xaa Xaa Phe Phe Xaa Xaa Tyr 1 5 <210> 19 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 19 Tyr Xaa Xaa Phe Phe Xaa Xaa Phe 1 5 <210> 20 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 20 Phe Xaa Xaa Phe Tyr Xaa Xaa Phe 1 5 <210> twenty one <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> twenty one Phe Xaa Xaa Tyr Phe Xaa Xaa Phe 1 5 <210> twenty two <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> twenty two Phe Xaa Xaa Tyr Tyr Xaa Xaa Phe 1 5 <210> twenty three <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> twenty three Tyr Xaa Xaa Tyr Tyr Xaa Xaa Phe 1 5 <210> twenty four <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> twenty four Phe Xaa Xaa Tyr Tyr Xaa Xaa Tyr 1 5 <210> 25 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 25 Tyr Xaa Xaa Tyr Tyr Tyr Xaa Xaa Tyr 1 5 <210> 26 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 26 Tyr Xaa Xaa Tyr Tyr Xaa Xaa Trp 1 5 <210> 27 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 27 Trp Xaa Xaa Tyr Tyr Xaa Xaa Tyr 1 5 <210> 28 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 28 Tyr Xaa Xaa Tyr Trp Xaa Xaa Tyr 1 5 <210> 29 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 29 Tyr Xaa Xaa Trp Tyr Xaa Xaa Tyr 1 5 <210> 30 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 30 Tyr Xaa Xaa Trp Trp Xaa Xaa Tyr 1 5 <210> 31 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 31 Trp Xaa Xaa Trp Trp Xaa Xaa Tyr 1 5 <210> 32 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (2)..(3) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <220> <221> MISC_FEATURE <222> (6) (7) <223> Xaa is selected from Arg (R), His (H), Lys (K), Glu (E), and Gln (Q). Asn (N) and Asp (D) <400> 32 Tyr Xaa Xaa Trp Trp Xaa Xaa Trp 1 5 <210> 33 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 33 Asn Phe Asn Phe Phe Phe Arg Phe Phe Phe 1 5 10 <210> 34 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 34 Trp Trp Trp Arg Trp Trp Trp Glu Trp Gln 1 5 10 <210> 35 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 35 Glu Phe Asn Phe Phe Phe Arg Phe Phe Phe 1 5 10 <210> 36 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 36 Asp Phe Glu Phe Phe Phe Arg Phe Phe Phe 1 5 10 <210> 37 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 37 Gln Phe Glu Phe Phe Phe Arg Phe Phe Phe 1 5 10 <210> 38 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 38 Glu Phe Glu Phe Phe Phe Arg Phe Phe Phe 1 5 10 <210> 39 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 39 Phe Phe Phe Arg Phe Phe Phe Glu Phe Gln 1 5 10 <210> 40 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 40 Phe Phe Phe Arg Phe Phe Phe Glu Phe Glu 1 5 10 <210> 41 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 41 Phe Phe Phe Arg Phe Phe Phe Glu Phe Asp 1 5 10 <210> 42 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 42 Phe Phe Phe Arg Phe Phe Phe Asn Phe Glu 1 5 10 <210> 43 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 43 Phe Phe Phe Arg Phe Phe Phe Asp Phe Glu 1 5 10 <210> 44 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 44 Phe Phe Phe Arg Phe Phe Phe Asn Phe Asn 1 5 10 <210> 45 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 45 Phe Phe Phe His Phe Phe Phe Glu Phe Gln 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 46 Phe Phe Phe His Phe Phe Phe Asn Phe Glu 1 5 10 <210> 47 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 47 Phe Phe Phe His Phe Phe Phe Glu Phe Asn 1 5 10 <210> 48 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 48 Glu Phe Asn Phe Phe Phe His Phe Phe Phe 1 5 10 <210> 49 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 49 Phe Phe Phe Arg Phe Phe Phe Glu Phe Asn 1 5 10 <210> 50 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 50 Phe Phe Phe His Phe Phe Phe Glu Phe Glu 1 5 10 <210> 51 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 51 Gln Phe Glu Phe Phe Phe His Phe Phe Phe 1 5 10 <210> 52 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 52 Phe Phe Phe His Phe Phe Phe Glu Phe Asp 1 5 10 <210> 53 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 53 Phe Phe Phe His Phe Phe Phe Asp Phe Glu 1 5 10 <210> 54 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 54 Tyr Tyr Tyr Arg Tyr Tyr Tyr Glu Tyr Gln 1 5 10 <210> 55 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 55 Asn Phe Glu Phe Phe Phe His Phe Phe Phe 1 5 10 <210> 56 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 56 Phe Phe Phe Lys Phe Phe Phe Lys Phe Glu 1 5 10 <210> 57 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 57 Glu Phe Asp Phe Phe Phe Arg Phe Phe Phe 1 5 10 <210> 58 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 58 Phe Phe Phe His Phe Phe Phe Asp Phe Asp 1 5 10 <210> 59 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 59 Phe Phe Phe His Phe Phe Phe Asn Phe Asn 1 5 10 <210> 60 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 60 Phe Phe Phe Arg Phe Phe Phe Asp Phe Asp 1 5 10 <210> 61 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 61 Phe Phe Phe Lys Phe Phe Phe Lys Phe Asn 1 5 10 <210> 62 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 62 Phe Phe Phe Lys Phe Phe Phe Glu Phe Glu 1 5 10 <210> 63 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 63 Phe Phe Phe Glu Phe Phe Phe Lys Phe Glu 1 5 10 <210> 64 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 64 Phe Phe Phe Gln Phe Phe Phe Gln Phe Gln 1 5 10 <210> 65 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 65 Phe Phe Phe Lys Phe Phe Phe Gln Phe Gln 1 5 10 <210> 66 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 66 Phe Phe Phe Lys Phe Phe Phe Asn Phe Asn 1 5 10 <210> 67 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 67 Phe Phe Phe Asn Phe Phe Phe Asn Phe Asn 1 5 10 <210> 68 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 68 Phe Phe Phe Lys Phe Phe Phe Glu Phe Gln 1 5 10 <210> 69 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 69 Phe Phe Phe Lys Phe Phe Phe Lys Phe Gln 1 5 10 <210> 70 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 70 Phe Phe Phe Lys Phe Phe Phe Gln Phe Lys 1 5 10 <210> 71 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 71 Phe Phe Phe Lys Phe Phe Phe Lys Phe Asp 1 5 10 <210> 72 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 72 Phe Phe Phe Lys Phe Phe Phe Asp Phe Asp 1 5 10 <210> 73 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 73 Phe Phe Phe Asn Phe Phe Phe Lys Phe Asn 1 5 10 <210> 74 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 74 Phe Phe Phe Asp Phe Phe Phe Asp Phe Asp 1 5 10 <210> 75 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 75 Phe Phe Phe Lys Phe Phe Phe Glu Phe Lys 1 5 10 <210> 76 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 76 Phe Phe Phe Lys Phe Phe Phe Asp Phe Lys 1 5 10 <210> 77 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 77 Phe Phe Phe Glu Phe Phe Phe Glu Phe Glu 1 5 10 <210> 78 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 78 Phe Phe Phe Asp Phe Phe Phe Lys Phe Asp 1 5 10 <210> 79 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 79 Phe Phe Phe Lys Phe Phe Phe Lys Phe Lys 1 5 10 <210> 80 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 80 Phe Phe Phe Glu Phe Phe Phe Lys Phe Lys 1 5 10 <210> 81 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 81 Phe Phe Phe Gln Phe Phe Phe Lys Phe Lys 1 5 10 <210> 82 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 82 Phe Phe Phe Lys Phe Phe Phe Asn Phe Lys 1 5 10 <210> 83 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 83 Phe Phe Phe Asn Phe Phe Phe Lys Phe Lys 1 5 10 <210> 84 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 84 Phe Phe Phe Gln Phe Phe Phe Lys Phe Gln 1 5 10 <210> 85 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 85 Phe Phe Phe Asp Phe Phe Phe Lys Phe Lys 1 5 10 <210> 86 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 86 Leu Leu Leu Arg Leu Leu Leu Glu Leu Gln 1 5 10 <210> 87 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 87 Phe Val Phe Lys Phe Val Phe Lys Phe Val 1 5 10 <210> 88 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 88 Cys Cys Cys Arg Cys Cys Cys Glu Cys Gln 1 5 10 <210> 89 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 89 Met Met Met Arg Met Met Met Glu Met Gln 1 5 10 <210> 90 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 90 Val Val Val Arg Val Val Val Glu Val Gln 1 5 10 <210> 91 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 91 Ile Ile Ile Arg Ile Ile Ile Glu Ile Gln 1 5 10 <210> 92 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 92 Gly Gly Gly Arg Gly Gly Gly Glu Gly Gln 1 5 10 <210> 93 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 93 Pro Pro Pro Arg Pro Pro Pro Glu Pro Gln 1 5 10 <210> 94 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 94 Thr Thr Thr Arg Thr Thr Thr Glu Thr Gln 1 5 10 <210> 95 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 95 Ala Ala Ala Arg Ala Ala Ala Glu Ala Gln 1 5 10 <210> 96 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 96 Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala 1 5 10 <210> 97 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 97 Ala Ala Ala Glu Ala Ala Ala Glu Ala Glu 1 5 10 <210> 98 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <400> 98 Ser Ser Ser Arg Ser Ser Ser Glu Ser Gln 1 5 10 <210> 99 ...

Claims

1. A peptide, wherein the peptide is RP182, and the sequence of the peptide is SEQ ID NO:

121.

2. A peptide, wherein the peptide is RP185, and the sequence of the peptide is SEQ ID NO:

123.

3. A pharmaceutical composition comprising a peptide as described in any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier, wherein the composition further comprises a chemotherapeutic agent selected from the group consisting of gemcitabine and docetaxel.

5. Use of the pharmaceutical composition according to any one of claims 3-4 in the preparation of a medicament for treating symptoms associated with chronic inflammation, wherein the medicament may be administered to a subject suffering from said symptoms.

6. Use of the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject suffering from said cancer.

7. The application as described in claim 5, wherein the subject is a mammal.

8. The application as described in claim 7, wherein the subject is a human being.

9. The application of claim 5, wherein the application reduces the level of at least one pro-inflammatory cytokine selected from the group consisting of: TNFα, IL1, IL6, IL12, MMP-1, MMP-9, MCP-1, IL8, IL17, and IL23.

10. The application of claim 9, wherein the level of the at least one cytokine is reduced by at least 10%.

11. The application as described in claim 6, wherein the subject is a mammal.

12. The application as described in claim 11, wherein the subject is a human being.

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