Peptide Therapeutics for Treating Alzheimer's Disease and Related Conditions - Patent application

Abstract

Peptide compounds derived from cathepsin G (CG), neutrophil elastase, and 37 kDa cationic antimicrobial protein (CAP37), and methods of their use in inhibiting and / or reversing the polymerization of amyloid beta peptide into oligomers and / or fibrils and / or disaggregating amyloid beta plaques, and methods of use of the peptide compounds in the treatment of, for example, Alzheimer's disease, neuroinflammation, and cerebral amyloid angiopathy.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 682,455, filed June 6, 2018, which is expressly incorporated herein by reference in its entirety.

[0002] government support This invention was made with Government support under Grant Nos. R21EY026229 and P20GM103640-06 awarded by the National Institutes of Health. The Government has certain rights in this invention. [Background technology]

[0003] Alzheimer's disease (AD) is the most common cause of dementia among people aged 65 years or older and the sixth leading cause of death in the United States. It currently affects approximately 5 million people, a number that is expected to double over the next 20 years. Currently, AD cannot be cured, prevented, or delayed, so there is a critical need for the development of efficient therapeutic approaches.

[0004] It has previously been shown that cationic antimicrobial protein of 37 kDa (CAP37) is significantly upregulated in neurons and hippocampal vasculature in patients with AD compared to age-matched controls. It has also been shown that CAP37 protein binds and cleaves amyloid beta (amyloid β, or Aβ), the major component of amyloid plaques found in the brains of patients with AD, and that CAP37 protein interacts with the proinflammatory receptor for advanced glycation end products (RAGE). Aβ accumulates in the brain early during the progression of AD and is a key hallmark of AD pathology. As its concentration increases, Aβ polymerizes, initially forming soluble oligomers and fibrils, which subsequently precipitate to form insoluble amyloid plaques. Aβ accumulation in the brain may be the result of (1) increased generation from cleavage of amyloid precursor protein (APP), (2) increased influx from the blood, and / or (3) decreased clearance.

[0005] RAGE belongs to the immunoglobulin superfamily of transmembrane receptors and mediates proinflammatory signals. Aβ (in the form of monomers, oligomers, and fibrils) is a known ligand of RAGE. Other known ligands of RAGE include advanced glycation end products (AGEs), S100 / calgranulin, and high-mobility group box 1 (HMGB1) protein. RAGE is expressed at low levels in adult tissues and is upregulated by a positive feedback loop when the concentration of RAGE ligands increases. RAGE expression is upregulated in the brains of patients with AD. In AD development, RAGE is thought to play a role in mediating the toxic effects of Aβ oligomers and fibrils in neurons and microglial cells. In neurons, RAGE can mediate the induction of oxidative stress and hyperphosphorylation of tau. RAGE also mediates the activation of microglial cells, perpetuating the chronic underlying neuroinflammation associated with AD. At the blood-brain barrier, RAGE activation is thought to be involved in the breakdown of barrier function, another pathological feature associated with AD. Finally, RAGE mediates the entry of Aβ from the circulation into the brain through a transcytosis mechanism.

[0006] Previous findings have established that: (1) CAP37 expression is increased in neurons of patients with Alzheimer's disease (AD) more than in patients of the same age who have not been diagnosed with AD, establishing a positive correlation between the amount of CAP37 in the brain and the disease. This was not the case for two closely related proteins, neutrophil elastase (NE) and cathepsin G (CG). (2) regulation of CAP37, NE, and CG expression generally correlates with regulation of proteins that serve as ligands for the proinflammatory receptor for advanced glycation end products (RAGE); (3) CAP37 binds to RAGE, as well as to the Aβ peptide, a known ligand of RAGE, and NE and CG also bind to RAGE; (4) CAP37-RAGE and NE-RAGE interactions are inhibited by specific RAGE inhibitors; (5) CAP37, NE, and CG bind to Aβ; and (6) CAP37, NE, and CG exert protease activity on Aβ, cleaving it at several identified cleavage sites.

[0007] Thus, both Aβ and RAGE have been identified as important pharmacological targets in the development of AD, and the present disclosure is directed to the identification of drugs that target Aβ and RAGE and thus can be used to treat patients with AD and / or neuroinflammation. [Brief description of the drawings]

[0008] [Figure 1] Figure 1 shows the binding of amyloid beta 1-42 (Aβ1-42) to full-length CAP37, NE, and CG proteins. Binding is stronger for CAP37 and CG and is not significantly altered by the addition of antiproteases (phenylmethylsulfonyl fluoride (PMSF) or chymostatin). Binding of Aβ1-42 to NE is almost undetectable but is significantly increased in the presence of PMSF, which inhibits cleavage of Aβ1-42 by NE. [Diagram 2]Figure 1 shows the levels of Aβ1-42 binding to wild-type CAP37-derived peptides 20-44 (20-44 CC, 95-122, and 120-146 QR) and mutant CAP37-derived peptides (20-44 CS, 20-44 SC, 120-146 WR, 120-146 QH, and 120-146 WH). Aβ1-42 did not bind to peptide 95-122. [Diagram 3] FIG. 3 shows the levels of Aβ1-42 binding to the “5RMP” modified CAP37-derived peptide of FIG. 2 (two AEEA mini-PEG molecules and four consecutive arginines linked to the N-terminus of the peptide, and one arginine linked to the C-terminus of the peptide). [Figure 4] FIG. 1 is a graph showing the level of fibrillation (aggregation) of Aβ1-42 in the presence of the indicated concentrations of full-length CAP37, NE, or CG. The time for complete fibrillization of Aβ1-42 (without added protein) is indicated by the vertical dotted line. [Diagram 5] 1 is a graph showing the level of Aβ1-42 fibrillization (aggregation) in the presence of full-length CAP37, NE, or CG at various concentrations of protein. NE has the highest inhibitory effect on Aβ1-42 fibrillization, followed by CG and then CAP37. [Figure 6] Figure 1 shows that the protease inhibitor PMSF impairs the inhibitory effect of CAP37 on Aβ1-42 fibrillogenesis. The IC50 of CAP37 is increased 3.5-fold in the presence of PMSF, indicating that the inhibitory effect of CAP37 on fibrillogenesis is at least in part due to the cleavage of Aβ1-42. [Figure 7] Figure 1 shows that the protease inhibitor PMSF abolishes the inhibitory effect of NE on Aβ1-42 fibrillogenesis. The IC50 of NE is increased 36-fold in the presence of PMSF, indicating that the inhibitory effect of NE on fibrillogenesis is due, at least in part, to cleavage of Aβ1-42. [Figure 8]Figure 1 shows a direct correlation between NE cleavage of Aβ1-42 and inhibition of fibrillization, supporting the idea that NE inhibition of fibrillization is primarily mediated by cleavage of Aβ. This experiment was performed in the absence of PMSF. [Figure 9] Figure 1 shows the direct correlation between cleavage of Aβ1-42 by NE and inhibition of fibrillization. This experiment was performed in the presence of PMSF. [Figure 10] Figure 1 shows that the protease inhibitor chymostatin abolishes the inhibitory effect of CG on Aβ1-42 fibrillogenesis. The IC50 of CG is increased 17-fold in the presence of chymostatin, indicating that the inhibitory effect of CG on fibrillogenesis is due, at least in part, to cleavage of Aβ1-42. [Figure 11] 1 shows a direct correlation between CG cleavage of Aβ1-42 and inhibition of fibrillization, supporting the idea that CG inhibition of fibrillization is primarily mediated by Aβ cleavage. This experiment was performed in the absence of chymostatin. [Figure 12] Figure 1 shows the direct correlation between cleavage of Aβ1-42 by CG and inhibition of fibrillization. The experiment was performed in the presence of chymostatin. [Figure 13] Figure 1 shows that CAP37-derived peptides 120-146 WR and 120-146 WR 5RMP inhibit, but not peptide 95-122 5RMP, fibrosis. [Figure 14] FIG. 1 shows that Aβ1-42 oligomers are more toxic to neurons than fibrils, with the monomeric form of Aβ1-42 being the least toxic. [Figure 15] FIG. 1 shows that NE and CG, but not CAP37, inhibit Aβ1-42 toxicity when incubated under conditions that favor fibril formation. [Figure 16] Figure 1 shows the effect of Aβ1-42 oligomers on neuronal cells in the presence of various concentrations of NE. NE significantly inhibited Aβ1-42 oligomer toxicity in a dose-dependent manner. [Figure 17]Figure 1 shows the effect of Aβ1-42 oligomers on neuronal cells in the presence of various concentrations of CG. CG significantly inhibited Aβ1-42 oligomer toxicity in a dose-dependent manner. [Figure 18] Figure 1 shows the effect of Aβ1-42 oligomers on neuronal cells in the presence of various concentrations of CAP37 protein.Full-length CAP37 does not inhibit Aβ1-42 oligomer toxicity. [Figure 19] Figure 1 shows the effect of Aβ1-42 oligomers on neuronal cells in the presence of various concentrations of CAP37-derived peptide 120-146 WR. The modified CAP37 peptide significantly inhibited Aβ1-42 oligomer toxicity in a dose-dependent manner. [Figure 20] Figure 1 shows the effect of Aβ1-42 oligomers on neuronal cells in the presence of various concentrations of the CAP37-derived peptide 120-146 WR-5RMP. The 5RMP modified CAP37 peptide variant significantly inhibited Aβ1-42 oligomer toxicity in a dose-dependent manner. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description In at least certain embodiments, the present disclosure is directed to peptide compounds containing peptide sequences obtained or derived from three neutrophil granule proteins, cathepsin G (CG), neutrophil elastase (NE), and cationic antimicrobial protein of 37 kDa (CAP37), methods of their use in inhibiting amyloid beta (Aβ) fibril formation and oligomerization, and methods of their use as therapeutics for treating, alleviating, and / or inhibiting Aβ-related diseases and conditions, including, for example, AD, cerebral amyloid angiopathy, dementia, and / or neuroinflammation, and / or symptoms thereof. CAP37, NE, and CG inhibit Aβ. 1-42It has been discovered that CAP37 can cleave Aβ (a 42 amino acid form of Aβ) at different sites and with different kinetics. It has also been observed that CAP37, but not NE or CG, is upregulated in the brains of patients with Alzheimer's disease (AD). CAP37 has been found to bind to RAGE, similar to the binding of RAGE to its known ligand, the Aβ peptide. NE and CG also bind to RAGE. CAP37-RAGE and NE-RAGE interactions are inhibited by certain RAGE inhibitors. Aβ 1-42 It is hypothesized that the binding and cleavage of CAP37, NE, and CG will inhibit its ability to form toxic oligomers and fibrils, and thus the present disclosure describes the results of whether CAP37, NE, and CG, and their peptide derivatives, can inhibit Aβ aggregation (fibril formation). It is believed that oligomeric and polymeric forms of Aβ are more toxic than monomeric forms. Thus, such inhibition will reduce the toxicity of Aβ and slow the progression of AD.

[0010] Without wishing to be bound by theory, it is believed that the peptide compounds of the present disclosure can bind to RAGE at the blood-brain barrier, thereby inhibiting the binding of systemically produced Aβ and thus its transport to the brain. The peptides, but not Aβ, will then be transported to the brain through the blood-brain barrier by RAGE-mediated transcytosis. Once in the brain, the peptides inhibit Aβ oligomerization and / or polymerization, and cause disaggregation of aggregated Aβ (depolymerizing Aβ oligomers and fibrils), thereby reducing the toxic effects of Aβ and its deposition in amyloid plaques. Furthermore, the peptides bind RAGE and TLR4 on neurons and microglial cells, antagonizing their pro-inflammatory effects mediated by aggregated Aβ and other agonists, thereby reducing neuroinflammation.

[0011] Before further detailed description of various embodiments of the disclosed compositions and methods of their use, it should be understood that the disclosure is not limited in its application to the details of the methods and compositions as set forth in the following description. The description provided herein is intended for illustrative purposes only and is not intended to be interpreted in a limiting sense. The disclosure is capable of other embodiments or can be implemented or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning, and the embodiments are intended to be illustrative and not comprehensive. It should also be understood that the phraseology and terminology used herein are for the purpose of description and should not be considered as limiting as such, unless otherwise indicated. Furthermore, in the following detailed description, numerous specific details are set forth to provide a more complete understanding of the disclosure. However, it will be apparent to one skilled in the art that various embodiments of the disclosure can be implemented without these specific details. In other instances, features well known to those skilled in the art have not been described in detail to avoid unnecessarily complicating the description. All alternatives, permutations, modifications, and equivalents apparent to those skilled in the art are intended to be included within the scope of the disclosure as defined herein. Thus, it is understood that the following examples, including specific embodiments, serve to illustrate the practice of the disclosure, and that the particulars set forth are presented by way of example and for illustrative discussion of specific embodiments only, to provide what is believed to be a useful and readily understood description of procedures and principles and conceptual aspects of the inventive concepts. Thus, while the compositions and methods of the present disclosure have been described with reference to specific embodiments, it will be apparent to those skilled in the art that variations can be applied to the compositions and / or methods described herein, and in the steps or sequence of steps of the methods, without departing from the concept, spirit, and scope of the inventive concepts disclosed herein.

[0012] All patents, published patent applications, and non-patent publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains.Each patent, published patent application, and non-patent publication referred to anywhere in this application is expressly incorporated herein by reference in its entirety to the same extent as if each patent, published patent application, or non-patent publication were specifically and individually indicated and incorporated by reference.In particular, International Patent Publication Nos. 2014 / 089088 and 2014 / 172747, and US Patent Nos. 9096679, 9603896, 9624283, and 9862748 are expressly incorporated herein by reference in their entirety.

[0013] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include plurals and plural terms shall include the singular.

[0014] As utilized in accordance with the methods and compositions of the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0015] The word "a" or "an" when used with the term "comprising" in the claims and / or specification may mean "one," but it is also consistent with the meanings of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and / or," even if the disclosure supports a definition that refers only to alternatives and "and / or," unless expressly indicated to refer only to alternatives or the alternatives are mutually exclusive. The use of the term "at least one" is understood to include one, as well as any amount greater than one, including but not limited to 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or any integer contained therein. The term "at least one" can extend up to 100 or 1000 or more depending on the term to which it is attached; in addition, the amount of 100 / 1000 should not be considered limiting since higher limits may also produce satisfactory results. Additionally, use of the term "at least one of X, Y, and Z" is understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z.

[0016] As used in this specification and the claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0017] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and also, if order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations containing one or more repeats of an item or term, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. Typically, those skilled in the art will understand that there is no limit to the number of items or terms in any combination, unless otherwise clear from the context.

[0018] Throughout this application, the term "about" or "approximately" is used to indicate that a value includes the inherent variation of error for the composition, the method used to administer the composition, or the variation that exists among study subjects. As used herein, the modifier "about" or "approximately" is intended to include not only the exact value, amount, degree, orientation, or other qualified characteristic or value, but also to include some slight variations due to, for example, measurement error, manufacturing tolerance, observer error, and combinations thereof. The term "about" or "approximately" when used herein when referring to a measurable value, such as an amount, a time duration, etc., is intended to encompass, for example, a variation of ±20% or ±10% or ±5% or ±1% or ±0.1% from the specified value, such as such variations being reasonable to carry out the disclosed method and as would be understood by one of ordinary skill in the art. As used herein, the term "substantially" means that the event or circumstance described thereafter has occurred completely, or that the event or circumstance described thereafter has occurred to a large extent or degree. For example, the term "substantially" means that the subsequently described event or circumstance occurs at least 80% of the time, at least 90% of the time, at least 91% of the time, at least 92% of the time, at least 93% of the time, at least 94% of the time, at least 95% of the time, at least 96% of the time, at least 97% of the time, at least 98% of the time, or at least 99% of the time.

[0019] As used herein, any reference to "one embodiment" or "an embodiment" means that a particular element, feature, composition, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. The appearances of the phrase "in one embodiment" in various places in this specification do not necessarily all refer to the same embodiment.

[0020] As used herein, the terms "AEEA", "AEEEA", "AEEP", and "AEEEP" refer, in certain embodiments, to short polyethylene glycol molecules ("mini-PEGs") that form part of the compounds disclosed herein and have the following specific meanings.

[0021] The term AEEA refers to the N- or C-terminal group, -NH(CH2CH2O)2CH2CO- or NH2(CH2CH2O)2CH2CO-, derived from [2-(2-amino-ethoxy)-ethoxy]-acetic acid (also known as 8-amino-3,6-dioxaoctanoic acid).

[0022] The term AEEEA refers to the N- or C-terminal group, -NH(CH2CH2O)3CH2CO- or NH2(CH2CH2O)3CH2CO-, derived from {2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-acetic acid (also known as 11-amino-3,6,9-trioxaundecanoic acid).

[0023] The term AEEP refers to the N- or C-terminal groups, -NH(CH2CH2O)2CH2CH2CO- or NH2(CH2CH2O)2CH2CH2CO-, derived from [3-(2-amino-ethoxy)-ethoxy]-propanoic acid (also known as 9-amino-4,7-dioxanonanoic acid).

[0024] The term AEEEP refers to the N- or C-terminal groups, -NH(CH2CH2O)3CH2CH2CO- or NH2(CH2CH2O)3CH2CH2CO-, derived from [3-[2-(2-amino-ethoxy)-ethoxy]-ethoxy]-propanoic acid (also known as 12-amino-4,7,10-trioxadodecanoic acid).

[0025] Below is a list of other abbreviations used in this specification, along with the entire words or phrases they represent: AGE: Advanced glycation end products Aβ: Amyloid beta or amyloid beta ANOVA: Analysis of variance APP: Amyloid precursor protein CAP37: A cationic antimicrobial protein with a molecular weight of 37 KDa CG: Cathepsin G BCA: Bicinchoninic acid BSA: bovine serum albumin DAB: diaminobenzidine tetrahydrochloride BPI: Bactericidal Permeability Enhancer DAG: diacylglycerol EDTA: Ethylenediaminetetraacetic acid EGF: Epidermal growth factor EGFR: epidermal growth factor receptor ERK: Extracellular signal-regulated kinase FBS: Fetal bovine serum 5RMP: 5Arginine-miniPEG GCSF: Granulocyte colony-stimulating factor GM-CSF: Granulocyte-macrophage colony-stimulating factor GPCR: G protein-coupled receptor HB-EGF: Heparin-binding epidermal growth factor HBSS: Hanks' balanced salt solution HCEC: human corneal epithelial cells H&E: Hematoxylin and Eosin HGF: Hepatocyte growth factor HBD-1: Human beta-defensin-1 HMGB1: high mobility group box 1 IL-6: Interleukin-6 IL-8: Interleukin-8 IP-10: Interferon-inducible protein-10 KC: keratinocyte-derived chemokine KSFM: Keratinocyte serum-free medium LPS: lipopolysaccharide MCP-1: Monocyte chemotactic protein-1 NADP: Nicotinamide adenine dinucleotide phosphate NE: neutrophil elastase PBS: Phosphate-buffered saline PDGF-BB: Platelet-derived growth factor-BB PKC: Protein kinase C PMA: phorbol 12-myristate 13-acetate PMSF: Phenylmethylsulfonyl fluoride RAGE: Receptor for advanced glycation end products RIPA: Radioimmunoprecipitation ROS: reactive oxygen species SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis SFM: Serum-free medium TBS: Tris-buffered saline TBST: Tris-buffered saline TWEEN® 20 (Thermo Fisher Scientific, Pittsburg, PA) TGF-β: Transforming growth factor beta TNF-α: Tumor necrosis factor alpha CG 119-144 : Amino acids 119-144 of cathepsin G protein NE 119-145 : Amino acids 119-145 of neutrophil elastase CAP37 120-146 : Amino acids 120 to 146 of the CAP37 protein CG 20-47 : Amino acids 20-47 of cathepsin G protein NE 20-44 : Amino acids 20-44 of neutrophil elastase CAP37 20-44 : Amino acids 20 to 44 of the CAP37 protein

[0026] The following standard amino acid abbreviations are used herein: Alanine: ala: A, cysteine: cys: C, aspartic acid: asp: D, glutamic acid: glu: E, phenylalanine: phe: F, glycine: gly: G, histidine: his: H, isoleucine: ile: I, lysine: lys: K, leucine: leu: L, methionine: met: M, asparagine: asn: N, glutamine: gln: Q, proline: pro: P, arginine: arg: R, serine: ser: S, threonine: thr: T, valine: val: V, tryptophan: trp: W, and tyrosine: tyr: T.

[0027] The term "mutant" or "variant" is intended to refer to a protein, peptide, nucleic acid, or organism that has at least one amino acid or nucleotide that differs from the wild-type version of the protein, peptide, nucleic acid, or organism, including, but not limited to, point substitutions, multiple consecutive or non-consecutive substitutions, insertions, chimeric, or fusion proteins, and the nucleic acids encoding them. Examples of conservative amino acid substitutions include, but are not limited to, substitutions that occur within the same group, such as within the group of basic amino acids (e.g., arginine, lysine, histidine), acidic amino acids (e.g., glutamic acid and aspartic acid), polar amino acids (e.g., glutamine and asparagine), hydrophobic amino acids (e.g., leucine, isoleucine, and valine), aromatic amino acids (e.g., phenylalanine, tryptophan, tyrosine), and small amino acids (e.g., glycine, alanine, serine, threonine, methionine). Other examples of possible substitutions are described below.

[0028] As used herein, the terms "peptide," "peptide analog," "peptide derivative," or "peptide compound" may refer to molecules that contain only amino acids, or to molecules that contain amino acids and one or more non-amino acid structures (e.g., PEG units). The terms "peptide," "peptide analog," "peptide derivative," or "peptide compound" may refer to variants ("mutants") of a "wild-type" peptide, or to molecules that contain amino acids and one or more non-amino acid structures (e.g., PEG units).

[0029] The term "amyloid beta" (Aβ) refers to Aβ peptides containing either 1-40 or 1-42 amino acids, or other forms, unless otherwise specifically specified.

[0030] The term "pharmacologically acceptable" refers to compounds and compositions that are suitable for administration to humans and / or animals without undue adverse side effects, such as toxicity, irritation, and / or allergic response, commensurate with a reasonable benefit / risk ratio.

[0031] "Bioactive" refers to the capacity to alter the physiological system of an organism, regardless of how the active agent produces its physiological effect.

[0032] As used herein, "pure" or "substantially pure" means that the target species is the predominant species present (i.e., on a molar basis, it is more abundant than any other target species in the composition), and in particular, a substantially purified fraction is a composition in which the target species constitutes at least about 50 percent (on a molar basis) of the total macromolecular species present. Generally, a substantially pure composition will constitute greater than about 80%, more particularly greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99% of the total macromolecular species present in the composition. The terms "pure" or "substantially pure" also refer to a preparation in which the target species (e.g., a peptide compound) is at least 60% (w / w) pure, or at least 70% (w / w) pure, or at least 75% (w / w) pure, or at least 80% (w / w) pure, or at least 85% (w / w) pure, or at least 90% (w / w) pure, or at least 92% (w / w) pure, or at least 95% (w / w) pure, or at least 96% (w / w) pure, or at least 97% (w / w) pure, or at least 98% (w / w) pure, or at least 99% (w / w) pure, or 100% (w / w) pure.

[0033] The terms "subject" and "patient" are used interchangeably herein and are understood to refer to warm-blooded animals, particularly mammals.Non-limiting examples of animals within the scope and meaning of this term include dog, cat, rabbit, rat, mouse, guinea pig, chinchilla, hamster, ferret, horse, pig, goat, cow, sheep, zoo animal, camel, llama; non-human primate, including old and new world monkeys and non-human primates (e.g., cynomolgus monkeys, chimpanzees, rhesus monkeys, orangutans and baboons); and human beings.

[0034] As used herein, the term "active agent" refers to a compound or composition having biological activity as described herein.

[0035] "Treatment" refers to therapeutic treatment. "Prevention" refers to prophylactic or preventative treatment measures. The term "treating" refers to the administration of a composition to a patient for therapeutic purposes.

[0036] The terms "therapeutic composition" and "pharmaceutical composition" refer to an active agent-containing composition that can be administered to a subject by any method known in the art or otherwise contemplated herein, where administration of the composition causes a therapeutic effect as described elsewhere herein. In addition, the compositions of the present disclosure can be designed to provide delayed, controlled, extended, and / or sustained release using formulation techniques well known in the art.

[0037] The term "effective amount", when used in the manner of the inventive concept, refers to the amount of active agent that is sufficient to show a detectable therapeutic effect without excessive adverse side effects (e.g., toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio. The effective amount for a patient depends on the type of patient, the size and health of the patient, the nature and severity of the condition to be treated, the method of administration, the duration of treatment, the nature of the concomitant therapy (if any), the specific formulation used, and the like. Therefore, it is not possible to specify the exact effective amount in advance. However, the effective amount for a given situation can be determined by those skilled in the art using routine experimentation based on the information provided herein.

[0038] The term "ameliorate" refers to a detectable or measurable improvement in a subject's condition, disease, or symptoms thereof. Detectable or measurable improvement includes subjective or objective reduction, reduction, inhibition, suppression, restriction, or control of the incidence, frequency, severity, progression, or duration of a condition or disease, or improvement of the symptoms or underlying causes or consequences of a disease, or reversal of a disease. Successful treatment results can result in a "therapeutic effect" or "benefit" of ameliorating, reducing, reducing, inhibiting, suppressing, restricting, controlling, or preventing the incidence, frequency, severity, progression, or duration of a disease or condition, or the prognosis of a disease or condition in a subject.

[0039] A reduction or reduction in deterioration, such as stabilizing a condition or disease, is also a successful treatment outcome. Thus, therapeutic benefit does not require complete disappearance or improvement of a disease or condition, or any one, most, or all of the adverse symptoms, complications, prognosis, or underlying causes associated with a disease or condition. Thus, a satisfactory end point may be achieved when there is a partial reduction, reduction, inhibition, suppression, restriction, control, or prevention in the incidence, frequency, severity, progression, or duration of a condition or disease, or a gradual improvement, such as inhibition or improvement (e.g., stabilization) over a short or long duration of a condition or disease. The effectiveness of a method or use, such as a treatment, that brings about a potential therapeutic benefit or improvement of a condition or disease can be confirmed by various methods and test assays.

[0040] The term "peptide" or "peptide sequence" is used herein to refer to a series of amino acid residues connected one to the other, typically by peptide bonds between the alpha-amino and carbonyl groups of adjacent amino acids forming an amino acid sequence. In certain embodiments, a peptide is a peptide having a length of 5 to 15, 25, 40, 60, 75 or more amino acids, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 1 The length of a fusion protein may range from 7, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60-75 or more amino acids. The term "polypeptide" or "protein" is used herein to refer to a series of amino acid residues that is longer in length than a single peptide, typically connected one to the other by peptide bonds between the alpha-amino and carbonyl groups of adjacent amino acids. A "fusion protein" or "fusion polypeptide" refers to (and may be used interchangeably with) a protein or polypeptide that has been produced by recombinant or synthetic methods to combine peptides in a contiguous configuration. In certain embodiments, the CAP37, NE, and CG peptide derivatives described elsewhere herein may be truncated, for example, by 1, 2, 3, 4, or 5 amino acids at one or both ends, so long as the resulting variant peptide retains the biological activity described herein related to inhibiting Aβ oligomerization and / or polymerization and / or disaggregation of Aβ. In other embodiments, the variant peptides may include an insertion of 1, 2, or 3 amino acids.

[0041] The peptides of the present disclosure, and the nucleic acids encoding them, include peptide and nucleic acid variants that contain natural amino acid or base substitutions (conservative or non-conservative). For example, peptide variants include, but are not limited to, variants that are not exactly the same as the sequences disclosed herein, but have additional substitutions of amino acid residues (conservative or non-conservative) in addition to the substitutions explicitly described for the various sequences listed herein, that do not substantially impair the activity or properties of the variants described herein. Examples of such conservative amino acid substitutions include: ala to gly, ser, or thr; arg to gln, his, or lys; asn to asp, gln, his, lys, ser, or thr; asp to asn or glu; cys to ser; gln to arg, asn, glu, his, lys, or met; glu to asp, gln, or lys; gly to pro or ala; his to arg, asn, gln, or tyr; ile to leu, met, or va. These may include, but are not limited to, l; leu to ile, met, phe, or val; lys to arg, asn, gln, or glu; met to gln, ile, leu, or val; phe to leu, met, trp, or tyr; ser to ala, asn, met, or thr; thr to ala, asn, ser, or met; trp to phe or tyr; tyr to his, phe, or trp; and val to ile, leu, or met.

[0042] Those skilled in the art will easily know how to make, identify, select, or test such variants for their binding activity to the same receptor targeted by non-variant peptide.Specific examples of conservative amino acid substitutions include, but are not limited to, gly:ala substitution; val:ile:leu substitution; asn:glu:his substitution; asp:glu substitution; ser:thr:met substitution; lys:arg:his substitution; and phe:tyr:trp substitution.Other types of substitutions, modifications, additions, deletions, and derivatives that produce functional variant peptides are also encompassed by the present disclosure, and those skilled in the art will easily know how to make, identify, or select such variants or derivatives, and test their receptor binding activity.

[0043] In certain embodiments, the present disclosure is directed to peptide compounds made up in whole or in part of one or more of the following amino acid sequences: CG 119-144 :GTLCTVAGWGRVSMRRGTDTLREVQL (SEQ ID NO: 1), NE 119-145 : GVQCLAMGWGLLGRNRGIASVLQELNV (SEQ ID NO: 2), CAP37 120-46 :GTRCQVAGWGSQRSGGRLSRFPRFVNV (SEQ ID NO: 3), CG 20-47 : IQSPAGQSRCGGFLVREDFVLTAAHCWG (SEQ ID NO: 4), NE 20-44 :LRGGHFCGATLIAPNFVMSAAHCVA (SEQ ID NO:5), and CAP37 20-44 :NQGRHFCGGALIHARFVMTAASCFQ (sequence number 6).

[0044] More particularly, the disclosure includes, but is not limited to, peptide variants that contain specific substitutions such as those described below.

[0045] In certain non-limiting embodiments, CG containing the following substitutions: 119-144 Variants of (SEQ ID NO:1) can be used to form peptide compounds used herein: one or more of the four basic arginine residues (positions 11, 15, 16, 22) can be changed to lysine or histidine. The acidic residue aspartic acid at position 19 can be changed to glutamic acid, and / or glutamic acid at position 23 can be changed to aspartic acid. One or more of the threonine residues at positions 2, 5, 18, and 20 can be changed to another hydrophilic residue (asparagine, glutamine, serine, tyrosine) or to another small residue (serine, alanine, glycine, valine, proline). One or more of the two other hydrophilic residues, serine at position 13 and glutamine at position 25, can be similarly changed to another hydrophilic residue (asparagine, glutamine, serine, threonine, or tyrosine). One or more of the other residues in this sequence (which are hydrophobic) can be substituted with another hydrophobic residue (alanine, glycine, cysteine, valine, proline, leucine, isoleucine, methionine, phenylalanine, tryptophan).

[0046] In other non-limiting embodiments, NE includes the following substitutions: 119-145Variants of (SEQ ID NO:2) can be used to form the peptide compounds used herein: the aromatic tryptophan residue at position 9 can be changed to another aromatic residue (tyrosine or phenylalanine). The acidic residue glutamic acid at position 24 can be changed to aspartic acid. One or more of the two basic arginine residues at positions 14 and 16 can be changed to another basic amino acid (lysine or histidine). One or more of the polar residues glutamine (positions 3 and 23), asparagine (position 15), and serine (position 20) can be changed to any other polar residue (asparagine, glutamine, serine, threonine, or tyrosine). The serine at position 20 can also be changed to another small residue (threonine, alanine, glycine, valine, proline). One or more of the other residues in this sequence (which are hydrophobic) can be substituted with another hydrophobic residue (alanine, glycine, cysteine, valine, proline, leucine, isoleucine, methionine, phenylalanine, tryptophan).

[0047] In another non-limiting embodiment, CAP37 containing the following substitutions: 120-146Variants of (SEQ ID NO:3) can be used to form the peptide compounds used herein: one or more of the small hydrophobic glycine residues at positions 1, 8, 10, 15, 16 of this peptide can be changed to another hydrophobic amino acid (alanine, cysteine, valine, proline, leucine, isoleucine, methionine, phenylalanine, or tryptophan), or another small amino acid (alanine, serine, threonine, valine, or proline). Similarly, one, two, three, four, or all of the positively charged arginine residues at positions 3, 13, 17, 20, 23 can be changed to another basic amino acid (lysine or histidine). Another example for this sequence is changing one or more of the hydrophilic amino acids, threonine at position 2, glutamine at positions 5 and 12, and serine at positions 14 and 19, to a different hydrophilic residue, e.g., threonine can be changed to asparagine, glutamine, serine, or tyrosine; glutamine can be changed to asparagine, serine, threonine, or tyrosine; and serine can be changed to asparagine, glutamine, threonine, or tyrosine. One or more of the other residues in this sequence (which are hydrophobic) can be substituted with another hydrophobic residue (alanine, glycine, cysteine, valine, proline, leucine, isoleucine, methionine, phenylalanine, tryptophan).

[0048] In other non-limiting embodiments, CG 20-47Alternative variants of (SEQ ID NO: 4) can be used to form the peptide compounds used herein: in this sequence, the two negatively charged residues, glutamic acid and aspartic acid (at positions 17 and 18, respectively), can be changed to two glutamic acids or two aspartic acids, or can be reversed to aspartic acid and glutamic acid, respectively. One or more of the two positively charged arginine residues at positions 9 and 16 of this peptide can be conservatively changed to lysine or histidine, and the histidine residue at position 25 can be changed to arginine or lysine. One or more of the polar glutamine residues at positions 2 and 7 can be changed to asparagine, serine, threonine, or tyrosine; and one or more of the polar serine residues at positions 3 and 8 can be changed to asparagine, glutamine, threonine, or tyrosine. One or more of the other residues in this sequence (which are hydrophobic) can be substituted with another hydrophobic residue (alanine, glycine, cysteine, valine, proline, leucine, isoleucine, methionine, phenylalanine, tryptophan). One or more of the aromatic residues phenylalanine 13 and 19, and tryptophan 27 can be changed to another aromatic residue (phenylalanine, tryptophan, or tyrosine).

[0049] In other non-limiting embodiments, NE includes the following substitutions: 20-44Alternative variants of (SEQ ID NO:5) can be used to form the peptide compounds used herein: the positively charged arginine residue at position 2 of this peptide can be conservatively changed to lysine or histidine, and one or more of the two histidine residues at positions 5 and 22 can be changed to arginine or lysine. One or more of the two polar residues asparagine 15 and serine 19 can be changed to any other polar residue (asparagine, glutamine, serine, threonine, or tyrosine). One or more of the other residues in this sequence (which are hydrophobic) can be substituted to another hydrophobic residue (alanine, glycine, cysteine, valine, proline, leucine, isoleucine, methionine, phenylalanine, tryptophan). One or more of the phenylalanines at positions 6 and 16 can be changed to another aromatic residue, either tryptophan or tyrosine.

[0050] In another non-limiting embodiment, CAP37 containing the following substitutions: 20-44 Alternative variants of (SEQ ID NO:6) can be used to form the peptide compounds used herein: one or more of the two positively charged arginine residues at positions 4 and 15 of this peptide can be conservatively changed to lysine or histidine, and one or more of the two histidine residues at positions 5 and 13 can be changed to arginine or lysine. One or more of the three aromatic phenylalanine residues at positions 6, 16, 24 can be changed to the other aromatic residues tryptophan or tyrosine. One or more of the polar residues asparagine 1, glutamine 2 and 25, threonine 19, and serine 22 can be changed to any other polar residue (asparagine, glutamine, serine, threonine, or tyrosine). One or more of the other residues in this sequence (which are hydrophobic) can be substituted with another hydrophobic residue (alanine, glycine, cysteine, valine, proline, leucine, isoleucine, methionine, phenylalanine, tryptophan).

[0051] Additionally, the peptide compounds may be CG-C-C-D as shown in the sequence below (residues in bold indicate amino acids in the wild type sequence): 119-144 Peptide, NE 119-145 , CAP37 120-146 , C.G. 20-47 , N.E. 20-44 , or CAP37 20-44 The peptide may include a peptide having an amino acid sequence derived from

[0052] In at least one embodiment, the peptide compound is peptide CG having the following amino acid sequence (SEQ ID NO:7): 119-144 Includes derivatives of: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 In the sequence, [ka]

[0053] In an alternative embodiment, X of SEQ ID NO:7 17 and / or X 18 The positions may be altered by deletion, insertion, or substitution as shown in Table 1 below.

[0054] [Table 1]

[0055] In at least one embodiment, the peptide compound is peptide NE having the following amino acid sequence (SEQ ID NO:8): 119-145 Includes derivatives of: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 In the sequence, [ka]

[0056] In an alternative embodiment, X of SEQ ID NO:8 16 and / or X 17 The positions may be altered by deletion, insertion, or substitution as shown in Table 2 below.

[0057] [Table 2]

[0058] In at least one embodiment, the peptide compound is peptide CAP37, having the following amino acid sequence (SEQ ID NO:9): 120-146 Includes derivatives of: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 In the sequence, [ka]

[0059] In an alternative embodiment, X of SEQ ID NO:9 15 and / or X 16 The positions may be altered by deletion, insertion, or substitution as shown in Table 3 below.

[0060] [Table 3]

[0061] In at least one embodiment, the peptide compound is peptide CG having the following amino acid sequence (SEQ ID NO:10): 20-47 Includes derivatives of: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 In the sequence, [ka]

[0062] In at least one embodiment, the peptide compound is peptide NE having the following amino acid sequence (SEQ ID NO:11): 20-44 Includes derivatives of: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 In the sequence, [ka]

[0063] In at least one embodiment, the peptide compound is peptide CAP37, having the following amino acid sequence (SEQ ID NO:12): 20-44 Includes derivatives of: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 In the sequence, [ka]

[0064] In certain non-limiting embodiments, an effective amount or therapeutic dosage of a peptide compound of the present disclosure contains sufficient active agent to deliver about 0.001 μg / kg to about 100 mg / kg (weight of active agent / body weight of subject). For example, the composition delivers about 0.01 μg / kg to about 50 mg / kg, more particularly about 0.1 μg / kg to about 10 mg / kg, more particularly about 1 μg / kg to about 1 mg / kg. Practicing the method of the present disclosure can include administering to a subject an effective amount of the peptide compound in any suitable systemic and / or local formulation in an amount effective to deliver a therapeutic dosage of the active agent. In certain embodiments, the effective dosage can be in the range of about 1 μg / kg to about 1 mg / kg of active agent.

[0065] The practice of the disclosed method may include administering to a subject a therapeutically effective amount of the peptide compound in any suitable systemic and / or local formulation in an amount effective to deliver the dosages recited above. The dosage may be administered once, or multiple times (including but not limited to, for example, 1-5 times per day, or once or twice per week), or continuously by intravenous infusion, depending on, for example, but not limited to, the desired therapeutic effect. In one non-limiting example of the disclosed method of treatment, the variant peptide compound is provided in an IV infusion in the range of about 0.01 mg / kg body weight to about 10 mg / kg body weight once per day.

[0066] Administration of the peptide compounds for use in pharmaceutical compositions or for practicing the methods of the present disclosure can be accomplished in a variety of conventional ways, including, but not limited to, orally, by inhalation, rectally, topically, nasally, or by dermal, subcutaneous, intraperitoneal, vaginal, or intravenous injection. Oral formulations can be formulated so that the peptide compound passes through parts of the digestive system before being released, for example, so that it may not be released until it reaches the small intestine or colon.

[0067] When an effective amount of the peptide compound is administered orally, it can be in the form of a solid or liquid preparation, such as a capsule, pill, tablet, lozenge, melt, powder, suspension, solution, elixir, or emulsion. A solid unit dosage form can be, for example, a capsule of the usual gelatin type containing surfactants, lubricants, and inert fillers, such as lactose, sucrose, and corn starch, or the dosage form can be a sustained release preparation. The pharmaceutical composition can contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules, and powders can contain about 0.05% to about 95% of the active substance compound, by dry weight. When administered in liquid form, a liquid carrier, such as water, petroleum, oils of animal or vegetable origin, such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils, can be added. The pharmaceutical composition in liquid form may further contain physiological saline, dextrose or other sugar solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains, in particular, about 0.005% to about 95% by weight of the active substance. For example, a dose of about 10 mg to about 1000 mg once or twice a day may be administered orally.

[0068] In another embodiment, the peptide compounds of the present disclosure can be tableted with conventional tablet bases such as lactose, sucrose, and corn starch in combination with binders such as gum acacia, corn starch, or gelatin, disintegrants such as potato starch or alginic acid, and lubricants such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the peptide compounds in an aqueous or non-aqueous pharma- ceutically acceptable solvent that may also contain suspending agents, sweeteners, flavorings, and preservatives, as known in the art.

[0069] For parenteral administration, for example, peptide compounds can be dissolved in physiologically acceptable pharmaceutical carriers and administered as either solution or suspension.The examples of suitable pharmaceutical carriers are water, saline, dextrose solution, fructose solution, ethanol, or oils of animal, vegetable, or synthetic origin.Pharmaceutical carriers can also contain preservatives and buffers, as is known in the art.

[0070] When an effective amount of the peptide compound is administered by intravenous, cutaneous, or subcutaneous injection, the compound is in the form of, inter alia, a pyrogen-free, parenterally acceptable aqueous solution or suspension. The preparation of such parenterally acceptable solutions, taking into consideration pH, isotonicity, stability, and the like, is well within the skill of one of ordinary skill in the art. Certain pharmaceutical compositions for intravenous, cutaneous, or subcutaneous injection may contain, in addition to the peptide compound, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicles as known in the art. The pharmaceutical compositions of the present disclosure may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of ordinary skill in the art.

[0071] As stated, the specific amount and mode of administration can be determined by one skilled in the art. Those skilled in the art who prepare formulations can use, for example, the methods described in Remington: The Science and Practice of Pharmacy, 22 nd Using formulation technology known in the art, such as those described in US Pat. No. 6,399,992, appropriate forms and modes of administration can be readily selected depending on the particular characteristics of the selected peptide compound, the condition to be treated, the stage of the condition, and other relevant circumstances.

[0072] Additional pharmaceutical methods can be used to control the duration of action of peptide compounds.Increased half-life and / or sustained release preparations can be achieved through the use of proteins or polymers that conjugate, complex with, and / or absorb peptide compounds, as previously discussed herein.Delivery control and / or increased half-life can be achieved by selecting appropriate polymers (such as, but not limited to, polysaccharides, polyesters, polyamino acids, homopolymers, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose or carboxymethylcellulose, and acrylamides such as N-(2-hydroxypropyl)methacrylamide) to control release, and appropriate concentrations of polymers, and methods of incorporation.

[0073] Another possible method useful in controlling the duration of action of the peptide compounds through sustained release preparations and half-life is the incorporation of the peptide compounds or their functional derivatives into particles of polymeric materials such as polyesters, polyamides, polyamino acids, hydrogels, poly(lactic acid), ethylene vinyl acetate copolymers, e.g., copolymer micelles of polyethylene glycol (PEG) and poly(l-aspartamide).

[0074] It is also possible to entrap the peptide compounds in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules, and poly(methyl methacrylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions, prepared, for example, by coacervation techniques or by interfacial polymerization. Such techniques are well known to those skilled in the art.

[0075] When the peptide compound is to be used as an injectable material, it can be formulated into a conventional injectable carrier. Suitable carriers include biocompatible, pharma- ceutically acceptable phosphate-buffered saline, particularly isotonic.

[0076] For the reconstitution of the lyophilized product according to the present disclosure, a sterile diluent may be used, which may contain materials that are generally recognized to approximate physiological conditions and / or are required by government regulations.In this regard, the sterile diluent may contain buffers to obtain a physiologically acceptable pH, such as sodium chloride, saline, phosphate buffered saline, and / or other materials that are physiologically acceptable and / or safe for use.In general, materials for intravenous injection in humans should comply with the regulations established by the US Food and Drug Administration, which are available to those skilled in the art.The pharmaceutical composition may also be in the form of an aqueous solution that contains many of the same materials as described above for the reconstitution of the lyophilized product.

[0077] The peptide compounds may also be administered as pharma- ceutically acceptable acid or base addition salts formed by reaction with inorganic acids such as hydrochloric, hydrobromic, perchloric, nitric, thiocyanic, sulfuric, and phosphoric acid, and organic acids such as formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, and fumaric acid, or by reaction with inorganic bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, tri-alkyl and aryl amines, and substituted ethanol amines.

[0078] In certain embodiments, the present disclosure includes a peptidic compound composition comprising: at least one peptidic compound coupled directly or indirectly to a carrier molecule, wherein at least one peptide of the peptidic compound is between 20 and 50 amino acids in length.

[0079] In at least certain embodiments, the present disclosure is directed to the use of full-length CAP37, NE, and CG proteins and / or peptide fragments thereof, and / or derivatives of such peptides, alone, in combination, or as peptide components of peptide compounds containing non-peptide moieties (e.g., PEG molecules), for the inhibition of the proinflammatory and neurotoxic effects of Aβ in Alzheimer's disease, cerebral amyloid angiopathy, and other neuroinflammatory conditions associated with Aβ. In non-limiting examples, peptide compounds of the present disclosure include peptides having the amino acid sequences disclosed above, SEQ ID NOs: 1-12.

[0080] The amino acid sequences described elsewhere herein can be modified by the addition of R, K, and / or H moieties (e.g., 1-10 amino acids linked to the N- and / or C-terminal portions of the peptide) and "mini-PEG" (AEEA, AEEEA, AEEP, and AEEEP) moieties linked to the N- and / or C-terminal portions of the tagged or untagged peptide sequence. Examples of such mini-PEG moieties are shown, for example, in WO 2014 / 089088 and WO 2014 / 172747, and U.S. Pat. Nos. 9,624,283 and 9,862,748.

[0081] Examples of CG-based, NE-based, and CAP37-based variant peptides that can be used in various embodiments of the peptide compounds of the present disclosure include, but are not limited to, those shown in Table 4.

[0082] [Table 4-1]

[0083] [Table 4-2]

[0084] In certain embodiments, the peptide compounds of the present disclosure are represented by formula (I): SX R -Pep-Y R (I) where Pep is an amino acid sequence disclosed or described herein; R and Y R are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R, K, or H residues, e.g., X R +Y R = up to 10; and S is a solubilizing moiety made up of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (i.e., 1-10) short PEG subunits, e.g., AEEA, AEEP, AEEEA, and AEEEP, in any combination, as defined elsewhere herein.

[0085] Peptide (X R -Pep-Y R ) -O(CH2) of the PEG subunit (S) attached to q The CO- moiety ("head group") is the (CH2) q It can be further modified to include several alternative embodiments of the moiety. These alternative embodiments, as well as those described above, can be characterized by formula (II): -O(CR1R2) q CO- (II) where R1 and R2 in formula II are side chain groups on C (i.e., "R1-C-R2"), q=0-4, and R1 and R2 are selected from H, CH3, and CH2CH3. When q=1, one or both of R1 and R2 can be selected from H, CH3, and CH2CH3. When q=2, one of the two R1 groups and one of the two R2 groups can be selected from H, CH3, and CH2CH3. When q=3, any of the three R1 groups and any of the three R2 groups can be selected from H, CH3, and CH2CH3. When q=4, any of the four R1 groups and any of the four R2 groups can be selected from H, CH3, and CH2CH3. Thus, in these non-limiting embodiments, the head group can include one or more substitutions for H on the carbons of the carbon backbone when C=1-4.

[0086] Examples of head group embodiments having formula II include, but are not limited to, the following: 1. -OCH2CH2CO- (e.g., as in AEEP) 2. -OCH2CO- (e.g., as in AEEA) 3. -OCH2CH2CH2CO-(q=3) 4. -OCH2CH2CH2CH2CO- (q=4, i.e., pentane head group) 5. -OC(CH3)2CO- (R1 and R2 = CH3, and q = 1) 6. -OCH2C(CH3)2CO- (R1 and R2 on the first carbon = H, and R1 and R2 on the second carbon = CH3, and q = 2) 7. -OCH2CH2CH2CH(CH3)CO- (R1=H and R2=CH3 on one carbon, and R1 and R2=H on every other carbon, and q=4) 8. -OCH2CH2CH2C(CH3)2CO- (R1 and R2=CH3 on one carbon and R1 and R2=H on all other carbons) 9. -OCH2CH2CH2CH(CH2CH3)CO- (R1=H and R2=CH2CH3 on one carbon, and R1 and R2=H on all other carbons) 10. -OCH(CH3) CH2CH2CH(CH2CH3)CO- (R1=H and R2=CH3 on one carbon, R1=H and R2=CH2CH3 on one carbon, and R1 and R2=H on all other carbons)

[0087] All stereoisomers of the peptide compounds formed based on the solubilizing unit described for formula II are intended to be included in the present disclosure. EXAMPLES

[0088] method Binding assays Enzyme-linked immunosorbent assay (ELISA) was used to quantify the binding of Aβ to CAP37, CAP37-derived peptides, NE, CG, and BSA (used as a negative control). CAP37, NE, and CG were purified from human neutrophils and purchased from Athens Research and Technology. BSA was from Sigma Aldrich. CAP37-derived peptides were synthesized by CS Bio Co with purity ≥95%. Maxisorp plates from Nunc were coated with 100 μl neutrophil proteins, peptides, or BSA diluted at 5 μg / ml in PBS with or without 1 mM PMSF (for experiments with CAP37, NE, and BSA) purchased from Sigma Aldrich, or ±125 μM chymostatin (for experiments with CG and BSA) purchased from Santa Cruz. Plate coating was performed at room temperature for 2 hours with shaking, then at 4° C. overnight. Plates were washed 3 times in PBST (PBS + 0.05% tween) and then blocked with 3% BSA in PBST for 1 hour at room temperature with shaking. Plates were washed 3 times in PBST and blocked with 150 nM Aβ 1-42(purchased from Bachem and reconstituted in 1 mM NaOH) was added to 0.1% BSA in PBST and incubated at 37° C. for 70 minutes. The plate was then washed 4 times with PBST and a monoclonal mouse anti-amyloid precursor protein / amyloid beta antibody purchased from Cell Signaling Technology was added at a 1:500 dilution in 1% BSA in PBST and incubated at room temperature with shaking for 1 hour. The plate was washed 4 times in PBST and a donkey anti-mouse HRP-conjugated secondary antibody from Jackson ImmunoResearch Laboratories was added at 1:10,000 in PBST and incubated at room temperature with shaking for 1 hour, then washed 4 times in PBST. Substrate buffer (49 mM citric acid, 102 mM sodium phosphate, pH adjusted to 5.0 with HCl, 7.5 mM substrate o-phenylenediamine from Kodak and 0.024% final H2O2 freshly added) was added to the plate and incubated in the dark for 30 minutes. Sulfuric acid (5N) was added to each well to stop the reaction and absorbance at 492 nm was read on a Biotek Synergy II plate reader.

[0089] Amyloid beta (Aβ) fibrillization assay The Amyloid Beta (1-42) Thioflavin T Aggregation Kit was purchased from Anaspec and used to assay Aβ IgG according to the manufacturer's instructions with some modifications. 1-42 The formation of peptide fibrils was monitored. Thioflavin T dye was diluted to 250 μM in fibrillation buffer A and kept in the dark until use. 1-42Peptides were suspended at 250 μg / ml (or 55 μM) in Buffer A, incubated on ice for 5 min, mixed by multiple inversions of the tube, sonicated for 5 min in a water bath sonicator at 4°C, mixed again, and centrifuged at 10,000xg for 5 min. The supernatant was transferred to a new tube and stored at 4°C until use. Inhibitors of aggregation, CAP37, CAP37-derived peptides, NE, CG, and BSA (used as a negative control) were diluted in water to 20x the desired final concentration. In low light, 10 μl Thioflavin T dye was added to a Corning low protein binding black plate and 85 μl Aβ prepared in Buffer A was added to a Corning low protein binding black plate. 1-42 , and 5 μl of water or the aggregation inhibitor to be tested were also added. Neutrophil proteins were tested in the absence and presence of protease inhibitors. PMSF was dissolved in 100% ethanol and used at 1 mM final concentration in reactions for CAP37 and NE. Chymostatin was dissolved in DMSO and used at 125 μM final concentration in reactions for CG. To ensure mixing, reactions were pipetted up and down twice in the wells with a multichannel pipette and fluorescence (λ Ex = 440 nm, λ Em = 485 nm) were read every 5 minutes for 3 hours on a BioTek Synergy 2 plate reader with the sensitivity set at 65 using Gen 5 software.

[0090] Enzyme activity assay Aβ treated with hexafluoroisopropanol 1-42 was purchased from Bachem and reconstituted at 5 mM in anhydrous DMSO. Reactions were performed with increasing concentrations of enzyme (CAP37, NE, or CG) and 10 μM Aβ in PBS. 1-42 The reaction was set up with substrate and incubated for 1 h at 37° C. The reaction was stopped by the addition of acetonitrile and trifluoroacetic acid (TFA) to final concentrations of 7.5% and 0.5%, respectively. Internal standard (Aβ from Bachem) dissolved in 10% acetic acid was added. 40-1) was added to a final concentration of 8 μg / ml. 10 μl aliquots of this mixture were desalted on C18 OMIX tips from Agilent Technologies. The C18 resin was first rinsed twice with 10 μl of 50% methanol and then twice with 10 μl of equilibration buffer (5% acetonitrile 0.5% TFA), then the sample was applied to the resin by pipetting 10 times through the resin, which was then washed twice with equilibration buffer and eluted with 75% acetonitrile 0.1% TFA.

[0091] Desalted samples were analyzed by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MARLDI-TOF) using a Bruker Ultraflex II instrument and Flex Control Software. Samples were spotted onto a steel plate with 1 μl of α-cyano-4-hydroxycinnamic acid matrix in 30% acetonitrile 0.1% TFA. Each sample was spotted in triplicate. Plates were dried in a vacuum desiccator. Each chromatograph was an average of 5×200 shots at 28% laser power in linear positive mode. Chromatographs were analyzed with Flex analysis software. Chromatographs were analyzed for Aβ. 40-1 The peaks at around 4,330 m / z corresponding to the internal standard and Aβ 1-42 There was a peak at around 4,515 m / z corresponding to the substrate. Aβ divided by the internal standard peak intensity 1-42 The ratio of peak intensities was calculated for each spot and triplicate spots were averaged to determine the amount of uncleaved Aβ in each enzymatic reaction.

[0092] Cell culture and neurotoxicity assays The mouse neuroblastoma cell line Neuro-2a from ATCC was used for these experiments. Cells were grown and seeded at 20,000 cells per well in 96-well plates in complete medium (MEMα, nucleosides, no phenol red, Gibco, with 10% heat-inactivated fetal bovine serum from Gibco and penicillin / streptomycin from Lonza). 24 hours after seeding, cells were washed with warm MEMα and then resuspended in 90 μl MEMα+N2 supplement+20 μl test sample (Aβ prepared as described below). 1-42 ) for 24 hours. Cells were incubated at 37°C for a further 24 hours and then dislodged by vigorous pipetting up and down. 10 μl of cells were added to 10 μl Trypan Blue dye (0.4% solution) from BioRad, mixed and counted in a BioRad TC20 cell counter. The percentage of live and dead cells was recorded for each well. For water and Triton X100 controls, 20 μl MEMα+N2 supplement was added in place of the test sample and 20 μl of medium was removed and replaced with 20 μl water or Triton X100 at a final concentration of 0.1% just before counting the cells.

[0093] Preparation of Aβ, monomers, fibrils, and oligomers test samples Monomeric Aβ from Bachem 1-42 (Hexafluoroisopropanol-treated Aβ 1-42 ) was reconstituted at 5 mM in anhydrous DMSO. Untreated Aβ from CS Bio 1-42 was also used in these experiments. It was first treated with 1 mM hexafluoroisopropanol from Sigma Aldrich, incubated at room temperature for 30 minutes, and left open in a fume hood overnight to dry. It was then vacuum dried at room temperature for 1 hour. 1-42 The dried film was stored at -20°C until use in order to keep it in monomeric form. Aβ 1-42 was also reconstituted at 5 mM in anhydrous DMSO prior to use.

[0094] Aβ 1-42 Toxicity of monomers was evaluated using freshly prepared Aβ 1-42 (5 mM in DMSO) was tested by diluting in MEMα+N2 supplement to a final concentration of 18 μM. This mixture was used to replace the complete growth medium in cells 24 hours after seeding and induce Aβ 1-42 The toxicity of the monomers was measured after 24 hours of incubation.

[0095] To prepare fibrillar and oligomeric test samples, monomeric Aβ 1-42 were subjected to conditions that favor the formation of either fibrils or oligomers. 1-42 was added to Anaspec fibrillation buffer A ± neutrophil protein and incubated at 37°C for 24 hours before being added to cells at a final concentration of 18 μM. Neutrophil protein was used at the Aβ / protein ratio that resulted in 50% inhibition of fibrillation (IC50) as previously determined for each protein in the fibrillation assay. MEMα+N2 supplement was used in place of fibrillation buffer A ± increasing concentrations of neutrophil protein or CAP37-derived peptide to form oligomers. Each mixture was then mixed with freshly prepared Aβ at a final concentration of 100 μM in DMSO. 1-42 and incubated at room temperature for 15 minutes. These test samples were then tested on the cells at a final concentration of 18 μM.

[0096] result Figure 1 shows Aβ 1-42 Figure 1 shows the binding of Aβ to full-length CAP37, NE, and CG proteins. Binding is stronger for CAP37 and CG and is not significantly altered by the addition of antiproteases (phenylmethylsulfonyl fluoride (PMSF) or chymostatin). 1-42 Binding of Aβ to NE was almost undetectable, whereas NE-mediated Aβ binding was 1-42 These results suggest that the Aβ binding to CAP37 and CG is more potent than that to other Aβ receptors. 1-42Figure 2 shows Aβ binding to wild-type CAP37-derived peptides 20-44 (20-44 CC, 95-122, and 120-146 QR) and mutant CAP37-derived peptides (20-44 CS, 20-44 SC, 120-146 WR, 120-146 QH, and 120-146 WH). 1-42 The levels of Aβ binding are shown. 1-42 did not bind to peptide 95-122. Figure 3 shows the binding of Aβ to the "5RMP" modified CAP37-derived peptide of Figure 2 (two AEEA mini-PEG molecules and four consecutive arginine residues linked to the N-terminus of the peptide, and one arginine linked to the C-terminus of the peptide). 1-42 These results show that Aβ 1-42 2A-C show that CAP37-derived peptides 20-44 and 120-146, both with and without the "5RMP" modification, bind to wild-type and mutant CAP37-derived peptides 20-44 and 120-146, both with and without the "5RMP" modification, but not to peptide 95-122, both with and without the "5RMP" modification.

[0097] Figures 4-7, 10, and 13 show the Aβ signaling pathway, recorded as relative fluorescence units (Rfu), in the absence and presence of increasing concentrations of three neutrophil granule proteins and specific wild-type and mutant CAP37-derived peptides. 1-42 Figure 4 shows the fibrillization of Aβ in the presence of the indicated concentrations of full-length CAP37, NE, or CG. 1-42 The fibrillation (aggregation) levels of Aβ (when no protein was added) were shown. 1-42 The time to complete fibrillization is indicated by the vertical dotted line. Fibrillization is either partially or completely inhibited in the presence of these proteins. Figure 5 shows the time to complete fibrillization of Aβ in the presence of full-length CAP37, NE, or CG at various concentrations of protein. 1-42 NE indicates the level of Aβ fibrillation (aggregation). 1-42 CAP37 has the highest inhibitory effect on fibrillation, followed by CG and then CAP37. Figure 5 shows the dose response performed with each full-length protein. The percent fibrillation shown in Figure 5 is the percentage of Aβ as shown by the dotted line in Figure 4. 1-42These dose-response experiments demonstrated that NE inhibits Aβ 1-42 The highest incidence of fibrosis (1 / 4,167 NE / Aβ 1-42 These results show that CAP37 has an inhibitory effect on CG (IC50 of 3.8 nM; molar ratio of 1 / 2,632) followed by CG (IC50 of 3.8 nM; molar ratio of 1 / 2,632) and CAP37 (IC50 of 876 nM; molar ratio of 1 / 11).

[0098] Figure 6 shows that the protease inhibitor PMSF inhibits Aβ binding to CAP37. 1-42 The IC50 of CAP37 was increased by 3.5-fold in the presence of PMSF, indicating that the inhibitory effect of CAP37 on fibrosis was at least partially mediated by Aβ 1-42 Figure 7 shows that the protease inhibitor PMSF inhibits the cleavage of Aβ from the NE. 1-42 The IC50 of NE was increased 36-fold in the presence of PMSF, indicating that the inhibitory effect of NE on fibrosis was at least partially mediated by Aβ 1-42 Three neutrophil granule proteins are involved in the cleavage of Aβ. 1-42 It has previously been found that Aβ cleaves 1-42 To determine whether cleavage of Aβ is required for inhibition of fibrillization, CAP37, NE, and CG were tested in the absence and presence of sufficient protease inhibitors (PMSF for CAP37 and NE, and chymostatin for CG). In all three experiments, Aβ 1-42 Inhibition of the enzymatic cleavage of Aβ also abolished the inhibitory effect of these proteins on fibrillogenesis, suggesting that the inhibitory effect on fibrillogenesis is at least in part due to Aβ 1-42 FIG. 13 shows a dose response performed with increasing concentrations of CAP37-derived peptides 95-122 5RMP, 120-146 WR 5RMP, and 120-146 WR. Peptide 95-122 5RMP inhibits Aβ 1-42Both peptides 120-146 WR 5RMP and 120-146 WR were able to interact with Aβ1-42 (Figs. 2 and 3) and inhibit Aβ fibrillation. The inhibitory effects of these CAP37-derived peptides were due to the fact that the peptides inhibited Aβ 1-42 Although the enzyme activity against Aβ was not observed, the activity was similar to that of full-length CAP37 (IC50 of about 1000 nM; molar ratio of about 1 / 10). 1-42 The cleavage of Aβ 1-42 This suggests that Aβ is not the only mechanism for the inhibition of fibrillation. 1-42 Direct binding to also appears to play a role in inhibiting fibrosis.

[0099] 8, 9, 11, and 12 show percent fibrillation and the corresponding Aβ on the right y-axis in experiments performed with increasing concentrations of full-length neutrophil granule protein in the absence and presence of protease inhibitors. 1-42 Figure 8 shows the percent cleavage of Aβ by NE. 1-42 Figure 9 shows a direct correlation between NE cleavage and inhibition of fibrillation. This correlation supports the idea that NE inhibition of fibrillation is primarily mediated by cleavage of Aβ. This experiment was performed in the absence of PMSF. Figure 9 shows the inhibition of Aβ by NE. 1-42 This experiment was performed in the presence of PMSF. 1-42 Figure 12 shows a direct correlation between CG cleavage and inhibition of fibrillation. This correlation supports the idea that CG inhibition of fibrillation is primarily mediated by cleavage of Aβ. This experiment was performed in the absence of chymostatin. Figure 12 shows the inhibition of Aβ by CG. 1-42 This experiment was performed in the presence of chymostatin. These results establish a direct correlation between Aβ cleavage and inhibition of fibrillation, and 1-42 These results support the idea that cleavage of β-lactamase is the primary mechanism explaining the inhibition of fibrillization mediated by the full-length protein.

[0100] Figure 14 shows the various higher-order structures of Aβ in neurons. 1-42 It shows the toxicity of Aβ. 1-42 Conditions were used that favor monomeric, oligomeric, or fibril conformations of Aβ. 1-42 It has been shown that oligomers are more toxic to neurons than fibrils. 1-42 These results confirm previous published results by other groups, showing that toxicity is highest for oligomers, followed by fibrils and then monomers.

[0101] Figure 15 shows that NE and CG inhibit Aβ when incubated under conditions that favor fibril formation. 1-42 Figure 15 shows that CAP37 inhibits the toxicity of Aβ formed in the absence or presence of neutrophil granule proteins used at concentrations that inhibit approximately 50% of fibrillation (IC50), as previously determined for each protein in Figure 5. 1-42 This experiment shows a significant inhibition of fibril toxicity by NE and CG. CAP37 inhibits Aβ fibril toxicity under these conditions. 1-42 In the fibril experiments, all three neutrophil granule proteins were incubated for 24 hours before addition to the cells to inhibit Aβ toxicity. 1-42 During this 24-hour fibrillation step, Aβ 1-42 The percent cleavage of Aβ by CAP37 is likely to be higher than 50%. In the case of NE and CG, cleavage is important for the inhibition of fibril toxicity. In contrast, Aβ 1-42 Cleavage of Aβ is involved in the inhibition of fibrillogenesis, as determined in Figure 6, but when preincubated under fibrillogenic conditions, 1-42 This is because NE and CG are unable to inhibit the toxicity of Aβ. 1-42This could be explained by the fact that CAP37 has more cleavage sites than CAP37, resulting in smaller products, and therefore the larger products generated by CAP37 cleavage may still be able to form toxic aggregates under fibrillogenic conditions.

[0102] 16-20 show the Aβ fibrosis profiles formed in the absence or presence of increasing concentrations of three neutrophil granule proteins and two CAP37-derived peptides that were found to inhibit fibrosis in FIG. 13. 1-42 Figure 16 shows the toxicity of Aβ oligomers in the presence of various concentrations of NE. 1-42 The effect of oligomers on neuronal cells. NE inhibits Aβ in a dose-dependent manner. 1-42 Significantly inhibited oligomer toxicity. NE was used at 0.5, 1, 2, and 4 times the IC50 determined in Figure 5. The results show significant inhibition of oligomer toxicity by NE, starting at 2x the IC50.

[0103] FIG. 17 shows the Aβ 1-42 The effect of oligomers on neuronal cells. CG inhibited Aβ in a dose-dependent manner. 1-42 Similar conditions as in Figure 16 were used in Figure 17 for CG, showing stronger inhibition of oligomer toxicity by CG, starting at 0.5 x IC50.

[0104] FIG. 18 shows the Aβ expression profile in the presence of various concentrations of CAP37 protein. 1-42 The effect of oligomers on neuronal cells is shown. Under the conditions used, full-length CAP37 inhibited Aβ 1-42 Notably, in these experiments with oligomers, all three neutrophil granule proteins inhibited Aβ only for 15 minutes prior to addition to the cells. 1-42 Aβ during the 15 min oligomerization step. 1-42The percent cleavage of is unknown. Thus, the importance of cleavage for inhibition of oligomerization and toxicity is unknown. As discussed above, it is possible that the larger products generated by CAP37 cleavage are still capable of forming toxic aggregates under oligomerization conditions.

[0105] FIG. 19 shows the effect of Aβ in the presence of various concentrations of the CAP37-derived peptide 120-146 WR. 1-42 The effect of oligomers on neuronal cells. The modified CAP37 peptide inhibited Aβ in a dose-dependent manner. 1-42 Figure 20 shows the effect of CAP37-derived peptide 120-146 WR-5RMP on Aβ toxicity in the presence of various concentrations of the peptide. 1-42 The effect of oligomers on neuronal cells. The 5RMP-modified CAP37 peptide variant inhibited Aβ in a dose-dependent manner. 1-42 In Figures 19 and 20, both Aβ 1-42 The peptides 120-146 WR and 120-146 WR 5RMP, which interact with Aβ (Figures 2 and 3) and inhibit fibrillization (Figure 13), were also able to significantly reduce the toxicity of oligomers. 1-42 It has no enzymatic activity against Aβ 1-42 The cleavage of Aβ 1-42 These results suggest that this is not the only mechanism for inhibition of Aβ oligomerization and toxicity. 1-42 Direct binding to may inhibit oligomerization.

[0106] Although the present disclosure is described in relation to certain specific embodiments so that its aspects may be more fully understood and appreciated, it is not intended that the present disclosure is limited to these specific embodiments.On the contrary, all alternatives, modifications, and equivalents are intended to be included within the scope of the present disclosure.Therefore, it is understood that the above examples, including specific embodiments, serve to illustrate the practice of the present disclosure, and the details shown are presented by way of example and for the purpose of illustrative discussion of specific embodiments only, in order to provide what is believed to be the most useful and easily understood explanation of the principles and conceptual aspects of the procedures, and methods and compositions of the present disclosure.Changes can be made in the formulation of the various compositions described herein, in the methods described herein, or in the steps or sequence of steps of the methods described herein, without departing from the spirit and scope of the present disclosure. The present invention may include the following aspects. [1] A peptide compound comprising a peptide having an amino acid sequence which is a derivative of a peptide of cathepsin G, neutrophil elastase, or cationic antimicrobial protein of 37 kDa (CAP37), provided that said amino acid sequence comprises at least one amino acid which differs from a wild-type sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6. [2] The amino acid sequence of the peptide is 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X22 X 23 X 24 X 25 X 26 (SEQ ID NO: 7), In the sequence, X 1 is G, X 2 is selected from A, F, G, I, L, M, P, S, T, W, and V; X 3 is selected from A, F, G, H, I, K, L, M, N, P, Q, R, V, and W; X 4 is selected from A, C, S, T, and V; X 5 is selected from A, F, G, I, L, M, P, S, T, W, and V; X 6 is selected from A, F, G, I, L, M, P, W, and V; X 7 is selected from A, F, G, I, L, M, P, W, and V; X 8 is G, X 9 is selected from A, F, G, I, L, M, P, W, and V; X 10 is G, X 11 is selected from A, C, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X 12 is selected from A, F, G, I, L, M, P, W, and V; X 13 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 14 is selected from A, F, G, I, L, M, P, W, and V; X 15 is selected from H, K, and R; X 16 is selected from C, H, K, N, Q, R, S, T, and Y; X 17 is G, X 18 is selected from C, N, Q, S, T, and Y; X 19 is selected from D and E; X 20 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 21 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 22 is selected from A, F, G, H, I, K, L, M, P, R, W, and V; X 23 is selected from L, C, D, E, F, G, H, I, K, A, M, N, P, Q, R, S, T, V, W, and Y; X 24 is selected from A, F, G, I, L, M, P, W, and V; X 25 is selected from C, N, Q, S, T, and Y; and X 26 is selected from A, F, G, I, L, M, P, W, and V; 2. The peptide compound of claim 1. [3] The amino acid sequence of the peptide is 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X25 X 26 X 27 (SEQ ID NO: 8), In the sequence, X 1 is G, X 2 is selected from A, F, G, I, L, M, P, S, T, W, and V; X 3 is selected from A, F, G, H, I, K, L, M, N, P, Q, R, V, and W; X 4 is selected from A, C, S, T, and V; X 5 is selected from A, F, G, I, L, M, P, S, T, W, and V; X 6 is selected from A, F, G, I, L, M, P, W, and V; X 7 is selected from A, F, G, I, L, M, P, W, and V; X 8 is G, X 9 is selected from A, F, G, I, L, M, P, W, and V; X 10 is G, X 11 is selected from A, F, G, I, L, M, P, W, and V; X 12 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 13 is selected from A, F, G, I, L, M, P, W, and V; X 14 is selected from H, K, and R; X 15 is selected from C, H, K, N, Q, R, S, T, and Y; X 16 is selected from A, F, G, H, I, K, L, M, P, R, W, and V; X 17 is G, X 18 is selected from D, A, E, F, G, I, L, M, P, W, and V; X 19 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 20 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 21 is selected from A, F, G, H, I, K, L, M, P, R, W, and V; X 22 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 23 is selected from C, N, Q, S, T, and Y; and X 24 is selected from A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X 25 is selected from A, F, G, I, L, M, P, W, and V; X 26 is selected from C, N, Q, S, T, and Y; and X 27 is selected from A, F, G, I, L, M, P, W, and V; 2. The peptide compound of claim 1. [4] The amino acid sequence of the peptide is 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X25 X 26 X 27 (SEQ ID NO: 9), In the sequence, X 1 is G, X 2 is selected from A, F, G, I, L, M, P, S, T, W, and V; X 3 is selected from A, F, G, H, I, K, L, M, N, P, Q, R, V, and W; X 4 is selected from A, C, S, T, and V; X 5 is selected from A, F, G, I, L, M, N, P, Q, S, T, W, and V, and X 6 is selected from A, F, G, I, L, M, P, W, and V; X 7 is selected from A, F, G, I, L, M, P, W, and V; X 8 is G, X 9 is selected from A, F, G, I, L, M, P, W, and V; X 10 is G, X 11 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 12 is selected from W, A, C, F, G, I, L, M, N, P, Q, S, T, V, and Y; X 13 is selected from C, H, K, N, Q, R, S, T, and Y; X 14 is selected from C, H, K, N, Q, R, S, T, and Y; X 15 is G, X 16 is selected from A, F, G, I, L, M, P, S, T, W, and V; X 17 is selected from D, A, E, F, G, I, K, L, M, P, R, S, T, V, W, and Y; X 18 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 19 is selected from A, C, F, G, I, L, M, N, P, Q, S, T, V, W, and Y; X 20 is selected from A, F, G, H, I, K, L, M, P, R, W, and V; X 21 is selected from A, F, G, I, L, M, P, V, W, and Y; X 22 is selected from A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X 23 is selected from A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X 24 is selected from A, F, G, I, L, M, P, W, and V; X 25 is selected from A, F, G, I, L, M, P, W, and V; X 26 is selected from C, N, Q, S, T, and Y; and X 27 is selected from A, F, G, I, L, M, P, W, and V; 2. The peptide compound of claim 1. [5] The amino acid sequence of the peptide is 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X26 X 27 X 28 (SEQ ID NO: 10), In the sequence, X 1 is selected from F, Y, W, A, V, I, L, and M; X 2 is selected from N, S, T, and Q; X 3 is selected from N, S, T, and Q; X 4 is selected from P, F, Y, W, A, V, I, L, M, and G; X 5 is selected from F, Y, W, A, V, I, L, and M; X 6 is selected from G, A, and V; X 7 is selected from N, S, T, and Q; X 8 is selected from N, S, T, and Q; X 9 is selected from R, H, and K; X 10 is selected from C, S, and T; X 11 is selected from G, A, and V; X 12 is selected from G, A, and V; X 13 is selected from F, Y, W, A, V, I, L, and M; X 14 is selected from F, Y, W, A, V, I, L, and M; X 15 is selected from F, Y, W, A, V, I, L, and M; X 16 is selected from R, H, and K; X 17 is selected from E, and D; X 18 is selected from E, and D; X 19 is selected from F, Y, W, A, V, I, L, and M; X 20 is selected from F, Y, W, A, V, I, L, and M; X 21 is selected from F, Y, W, A, V, I, L, and M; X 22 is selected from N, S, T, and Q; X 23 is selected from F, Y, W, A, V, I, L, and M; X 24 is selected from F, Y, W, A, V, I, L, and M; X 25 is selected from R, H, and K; X 26 is selected from C, S, and T; X 27 is selected from F, Y, W, A, V, I, L, and M; and X 28 is selected from G, A, and V; 2. The peptide compound of claim 1. [6] The amino acid sequence of the peptide is 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X23 X 24 X 25 (SEQ ID NO: 11), In the sequence, X 1 is selected from F, Y, W, A, V, I, L, and M; X 2 is selected from R, H, and K; X 3 is selected from G, A, and V; X 4 is selected from G, A, and V; X 5 is selected from R, H, and K; X 6 is selected from F, Y, W, A, V, I, L, and M; X 7 is selected from C, S, and T; X 8 is selected from G, A, and V; X 9 is selected from F, Y, W, A, V, I, L, and M; X 10 is selected from N, S, T, and Q; X 11 is selected from F, Y, W, A, V, I, L, and M; X 12 is selected from F, Y, W, A, V, I, L, and M; X 13 is selected from F, Y, W, A, V, I, L, and M; X 14 is selected from P, F, Y, W, A, V, I, L, M, and G; X 15 is selected from N, S, T, and Q; X 16 is selected from F, Y, W, A, V, I, L, and M; X 17 is selected from F, Y, W, A, V, I, L, and M; X 18 is selected from F, Y, W, A, V, I, L, and M; X 19 is selected from N, S, T, and Q; X 20 is selected from F, Y, W, A, V, I, L, and M; X 21 is selected from F, Y, W, A, V, I, L, and M; X 22 is selected from R, H, and K; X 23 is selected from C, S, and T; X 24 is selected from F, Y, W, A, V, I, L, and M; and X 25 is selected from F, Y, W, A, V, I, L, and M; 2. The peptide compound of claim 1. [7] The amino acid sequence of the peptide is 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 (SEQ ID NO: 12), In the sequence, X 1 is selected from N, S, T, and Q; X 2 is selected from N, S, T, and Q; X 3 is selected from G, A, and V; X 4 is selected from R, H, and K; X 5 is selected from R, H, and K; X 6 is selected from F, Y, W, A, V, I, L, and M; X 7 is selected from C, S, and T; X 8 is selected from G, A, and V; X 9 is selected from G, A, and V; X 10 is selected from F, Y, W, A, V, I, L, and M; X 11 is selected from F, Y, W, A, V, I, L, and M; X 12 is selected from F, Y, W, A, V, I, L, and M; X 13 is selected from R, H, and K; X 14 is selected from F, Y, W, A, V, I, L, and M; X 15 is selected from R, H, and K; X 16 is selected from F, Y, W, A, V, I, L, and M; X 17 is selected from F, Y, W, A, V, I, L, and M; X 18 is selected from F, Y, W, A, V, I, L, and M; X 19 is selected from N, S, T, and Q; X 20 is selected from F, Y, W, A, V, I, L, and M; X 21 is selected from F, Y, W, A, V, I, L, and M; X 22 is selected from N, S, T, and Q; X 23 is selected from C, S, and T; X 24 is selected from F, Y, W, A, V, I, L, and M; and X 25 is selected from N, S, T, and Q; 2. The peptide compound of claim 1. [8] 2. The peptide compound of claim 1, which is effective in inhibiting and / or reversing the polymerization of amyloid beta (Aβ) peptides into Aβ oligomers and / or Aβ fibrils, and / or causing disaggregation of Aβ plaques. [9] The Aβ peptide is Aβ 1-40 and Aβ 1-42 9. The peptide compound according to claim 8, which is at least one of:

[10] A method for inhibiting the formation of amyloid beta (Aβ) oligomers and / or Aβ fibrils in a subject in need of such treatment, comprising administering to the subject an amount of a peptide compound effective to inhibit and / or reverse the polymerization of amyloid beta (Aβ) peptides into Aβ oligomers and / or Aβ fibrils and / or effective to cause disaggregation of Aβ plaques.

[11] 11. The method of claim 10, wherein the peptide compound comprises a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12.

[12] A method for treating a disease or condition associated with amyloid beta (Aβ) peptide in a subject in need of such treatment, comprising administering to the subject an amount of a peptide compound effective to inhibit and / or reverse polymerization of Aβ peptide.

[13] 13. The method of claim 12, wherein the peptide compound comprises a peptide that is a derivative of cathepsin G (CG) selected from SEQ ID NO: 7 and SEQ ID NO: 10.

[14] 13. The method of claim 12, wherein the peptide compound comprises a peptide that is a derivative of neutrophil elastase (NE) selected from SEQ ID NO:8 and SEQ ID NO:11.

[15] 13. The method of claim 12, wherein the peptide compound comprises a peptide that is a derivative of a 37 kDa cationic antimicrobial protein (CAP37) selected from SEQ ID NO: 9 and SEQ ID NO: 12.

[16] 13. The method of claim 12, wherein inhibiting polymerization of Aβ peptide comprises inhibiting formation of Aβ oligomers.

[17] 13. The method of claim 12, wherein inhibiting polymerization of Aβ peptides comprises inhibiting formation of Aβ fibrils.

[18] 13. The method of claim 12, wherein reversing polymerization of Aβ peptides comprises causing disaggregation of Aβ oligomers, Aβ fibrils, or Aβ plaques.

[19] The Aβ peptide is Aβ 1-40 and Aβ 1-42 The method of claim 12, wherein the at least one of

Claims

1. A peptide compound comprising a peptide having the amino acid sequence of SEQ ID NO:20 or SEQ ID NO:

15.

2. 2. The peptide compound of claim 1, wherein the peptide of the peptide compound comprises the amino acid sequence of SEQ ID NO:

20.

3. 2. The peptide compound of claim 1, wherein the peptide of the peptide compound comprises the amino acid sequence of SEQ ID NO:

15.

4. The peptide compound according to any one of claims 1 to 3, wherein the peptide compound inhibits and / or reverses the polymerization of amyloid beta (Aβ) peptides into Aβ oligomers.

5. The peptide compound according to any one of claims 1 to 4, wherein the peptide compound inhibits and / or reverses the polymerization of Aβ peptides into Aβ fibrils.

6. The peptide compound of any one of claims 1 to 5, wherein the peptide compound is effective to cause disaggregation of Aβ plaques.

7. The Aβ peptide is Aβ １－４０ and Aβ １－４２ The peptide compound according to any one of claims 4 to 6, which is at least one of:

8. The peptide compound of any one of claims 1 to 7, wherein the peptide compound is conjugated to, incorporated into, complexed with, or entrapped within a polymer.

9. The peptide compound according to any one of claims 1 to 8, wherein the peptide consists of up to 50 amino acids.

10. The peptide compound of any one of claims 1 to 9, wherein the peptide compound comprises a polyethylene glycol moiety conjugated to the peptide.

11. A composition for use in inhibiting and / or reversing polymerization of amyloid beta (Aβ) peptide in a subject in need of such treatment, comprising a peptide compound according to any one of claims 1 to 10.

12. 12. The composition of claim 11, wherein inhibiting and / or reversing polymerization of Aβ peptide comprises inhibiting the formation of at least one of Aβ oligomers and Aβ fibrils.

13. 12. The composition of claim 11, wherein inhibiting and / or reversing polymerization of Aβ peptide comprises causing disaggregation of at least one of Aβ oligomers, Aβ fibrils, and Aβ plaques.

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