Novel peptides and uses thereof

Abstract

To provide novel peptides that bind to preselinin 1 and / or preselinin 2 binding-domains on β-APP and pharmaceutical compositions comprising the same, methods, and uses thereof.SOLUTION: The present invention provides a peptide comprising a sequence of Ac-DEEEDEEL-NH2, a sequence of dEEEDEEL- NH2 or a sequence of Ac-dEEEDEEL-NH2, a pharmaceutical composition comprising the peptide, and use of the peptide for treating a disease or disorder.SELECTED DRAWING: Figure 1A-B

Description

[Technical field]

[0001] This invention was made with Government support under R44AG043278 awarded by the National Institutes of Health (NIH). The Government has certain rights in this invention. CROSS-REFERENCE TO RELATED APPLICATIONS This application is incorporated herein by reference in its entirety, filed Jan. 7, 2019. This application claims the benefit of U.S. Provisional Patent Application No. 62 / 789,114. Sequence Listing This application was created on January 3, 2020, is 4,096 bytes in size, and has the following file name: 14461-003-228_SEQ_L Please refer to the sequence listing submitted with this application in text format named ISTING.txt. It's more embedded. (1. Field) Novel peptides that bind to the presenilin 1 and / or presenilin 2 binding domains on β-APP Provided herein are compounds that can be used to treat or prevent the development of inflammatory bowel disorders, as well as pharmaceutical compositions comprising same, methods and uses thereof. [Background technology]

[0002] (2.Background) Neurodegenerative disorders are progressive disorders characterized by the loss of specific neuronal populations and corresponding loss of neuronal function. Among various neurodegenerative disorders, it is characterized by progressive memory loss and cognitive decline. The most common form of Alzheimer's disease (AD) is the pulmonary edema that occurs when the brain is unable to function properly. The presence of amyloid plaques and neurofibrillary tangles in the brain. After cleavage by retase, the amyloid precursor protein (APP; Serrano-Pozo et al., 2011, Co ld Spring Harb Perspect Med. 1,1, a006189) They are formed by the extracellular deposition of amyloid beta (Aβ) (see Zhang et al., 2011, Mol. Brain 4, 3). ).

[0003] Presenilin 1 and 2 (PS-1 and PS-2) are the catalytic components of γ-secretase. Over 150 different mutations within S-2 have been identified in AD epidemiological studies and are being used to study Aβ peptide production. (Haas et al., 2012, Cold Spring Harb Perspect Med. 2(5): The production and accumulation of Aβ initiates a cascade of neurodegenerative events, contributing to the aging process in AD. This results in the formation of plaques and intraneurofibrillary tangles and neuronal loss (Greenfield et al., (See Golde, 2005, Brain Pathol. 15, 84-87; 2000, Front. Biosci. 5, D72-D83). Summary of the Invention

[0004] (3. Overview of Disclosure) In one embodiment, (i) the N-terminal amino acid Asp is acetylated and the C-terminal amino acid Leu is amidated. Can [ka] (ii) the N-terminal amino acid Asp is a D-amino acid and the C-terminal amino acid Leu is amidated [ka] or (iii) the N-terminal amino acid Asp is a D amino acid and is acetylated, and the C-terminal amino acid The acid Leu is amidated [ka] Provided herein is a peptide comprising the sequence:

[0005] In some embodiments, the peptide comprises: [ka] In some embodiments, the peptide comprises the sequence: [ka] In yet another embodiment, the peptide comprises the sequence: [ka] Contains an array of.

[0006] In another embodiment, a first domain comprising the sequence of SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5; and Provided herein are peptides that include the second domain.

[0007] In some embodiments, the second domain comprises an Fc domain. The second domain comprises a purified peptide.

[0008] In another aspect, a method for the preparation of a peptide comprising the peptide provided herein and a pharma- ceutical acceptable excipient is provided. Pharmaceutical compositions are provided herein.

[0009] In another embodiment, the basal protein is a basal protein that is a basal protein of presenilin-1 (PS-1) and / or presenilin-2 (PS-2) in a cell. A method for attenuating binding of β-amyloid precursor protein (β-APP) comprising the steps of: A method is provided herein that includes contacting a cell with a provided peptide or pharmaceutical composition. will be done.

[0010] In another aspect, a method for attenuating the production of amyloid beta in a cell comprises the steps of: A method is provided herein that includes contacting a cell with a provided peptide or pharmaceutical composition. will be done.

[0011] In another aspect, a method of attenuating amyloid beta levels in a subject is provided comprising the steps of: and administering to said subject a therapeutically effective amount of a peptide or pharmaceutical composition provided by Provided herein.

[0012] In some embodiments, the amyloid beta is amyloid beta 40. In other embodiments, The amyloid beta is amyloid beta42.

[0013] In yet another aspect, there is provided a method of treating a disease or disorder in a subject, comprising administering to a subject a compound as described herein. The method includes administering to the subject a therapeutically effective amount of the peptide or pharmaceutical composition provided herein. Provided in the specification.

[0014] In some embodiments, the disease or disorder is an amyloid (or amyloid beta)-related disease or disorder. disorders, diseases or disorders associated with amyloid fibril formation, aggregation or deposition, neurological disorders, Or a neurodegenerative disease.

[0015] In some embodiments, the disease or disorder is Alzheimer's disease, Parkinson's disease, trauma, The disease is selected from the group consisting of chronic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and dementia.

[0016] In some embodiments, the disease or disorder is associated with frontotemporal dementia, Pick's disease. Frontotemporal degeneration, vascular dementia, corticobasal degeneration, and ischemic vascular dementia (IVD) ), dementia with Lewy bodies, and Alzheimer's disease Or a dementia-related disease or disorder.

[0017] In some embodiments, the disease or disorder is an eye disorder or Down's syndrome. In one embodiment, the eye disorder is associated with Alzheimer's disease. In another embodiment, the eye disorder is associated with macular degeneration. In some embodiments, the macular degeneration is age-related macular degeneration (AMD).

[0018] In some embodiments, the disease or disorder is a transmissible spongiform encephalopathy, a cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis, mild cognitive impairment, sporadic inclusion body myositis and age-related macular degeneration The compound is selected from the group consisting of:

[0019] In yet another aspect, a method for improving memory in a subject comprises administering to a subject a therapeutically effective amount of the compound provided herein. Provided herein are methods comprising administering a therapeutically effective amount of a peptide or pharmaceutical composition to a subject. will be done.

[0020] A method of attenuating amyloid beta-induced activity in a subject, comprising administering to a subject a therapeutically effective amount of a compound as provided herein. The method includes administering to the subject a therapeutically effective amount of the peptide or pharmaceutical composition. It will be offered.

[0021] A method of inhibiting amyloid-β-induced activity in a subject, comprising administering to a subject a therapeutic agent provided herein. The method includes administering to the subject a therapeutically effective amount of the peptide or pharmaceutical composition provided herein. will be done.

[0022] A method of attenuating amyloid beta-induced activity in a cell, comprising the steps of: Provided herein are methods that include contacting the cells with an effective amount of a peptide or pharmaceutical composition. It will be offered.

[0023] A method of inhibiting production of tau protein in a subject, comprising administering to a subject a therapeutic agent provided herein. The method includes administering to the subject a therapeutically effective amount of the peptide or pharmaceutical composition provided herein. In one embodiment, the tau protein is a phosphorylated tau protein. In some embodiments, the tau protein is a hyperphosphorylated tau protein.

[0024] A method of attenuating tau protein levels in a subject, comprising administering to said subject a therapeutically effective amount of a tau protein .... The method includes administering to the subject a therapeutically effective amount of the peptide or pharmaceutical composition. In one embodiment, the tau protein is a phosphorylated tau protein. In embodiments, the tau protein is a hyperphosphorylated tau protein.

[0025] A method for inhibiting the production of tau protein in a cell, comprising administering an effective amount of Provided herein are methods comprising contacting a cell with a peptide or pharmaceutical composition of In one embodiment, the tau protein is a phosphorylated tau protein. The tau protein is a hyperphosphorylated tau protein.

[0026] A method of attenuating tau protein-inducing activity in a subject, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 4, further comprising administering to said subject ... The method includes administering to the subject a therapeutically effective amount of a peptide or pharmaceutical composition comprising the peptide or pharmaceutical composition described herein. Provided.

[0027] In some embodiments, the subject is a human subject. [Brief description of the drawings]

[0028] (4. BRIEF DESCRIPTION OF THE DRAWINGS) [Figure 1]1A-1D show the "mean concentration versus time" profiles of P8 (circles) and 8M2D (squares) in rat plasma and CSF following IV (FIGS. 1A and 1B) and SC (FIGS. 1C and 1D) administration.

[0029] [Diagram 2] FIG. 2 shows the mean 8M2D (mP8) plasma concentrations following SC administration in transgenic mice.

[0030] [Diagram 3] FIG. 3 shows the results of a pharmacodynamic (PD) assay described in Example 4, in which rats were subcutaneously dosed with different peptides and plasma Aβ40 was quantified at different time points after dosing, demonstrating that 8M2D can lower Aβ40 more effectively than P8 and 8M1D.

[0031] [Figure 4] Figure 4A shows the concentration of P8 in various brain regions, and Figure 4B shows Aβ analysis in the CSF of APP transgenic mice after administration of P8 (left panel) and 8M2D (middle and right panels). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] (5. Detailed Description) The present disclosure provides novel antibodies that specifically bind to the presenilin 1 and / or 2 binding domains on β-APP. The present invention provides peptides, pharmaceutical compositions containing same, methods and uses thereof. The present invention relates to a peptide capable of inhibiting the processing of β-APP into Aβ, a pharmaceutical composition containing the same, and The present invention provides methods and uses of the

[0033] Neurodegenerative disorders are characterized by the loss of specific neuronal populations and the corresponding loss of neuronal function. It is a progressive disease. The most consistent risk factor for the development of neurodegenerative disorders is aging (Tanner et al. (See, e.g., 1992, Neurol. Clin. 10:317-329.) These neurodegenerative disorders include, for example, arachidonic acid syndrome (ARS), Zheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (Przedborski et al., 2003, J Clin Invest. 111(1): 3-10).

[0034] Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population and progresses The most defining neuropathological feature of AD is the development of memory impairment and cognitive decline. The presence of amyloid plaques and neurofibrillary tangles in affected brains. Apo-apoptotic precursor protein (APP; Serrano-Pozo et al., 2011, Cold Spring Harb Perspective Med. 1,1, a006189) in the extracellular deposition of amyloid beta (Aβ), a proteolytic product of A subset of AD (<10%), familial early-onset AD (FAD), is more common than sporadic cases. AD is an autosomal dominant disorder with clinically identifiable symptoms at a very young age. Mutations in the genes encoding presenilins (PS-1 and PS-2) on chromosome 14 and 16 are the most common causes of FAD. (Levy-Lahad et al., 1995, Science 269, 97 3-977; see Sherrington et al., 1995, Nature 375, 754-760). Because the differences in pathological features are minimal, PS-1 and PS-2 are considered to be the most common form of AD, which constitutes the majority of cases. It is believed to be involved in the general pathogenesis of AD, including in cases of AD (Zhang et al., 2014, FR ont Cell Neurosci. 8, 427).

[0035] Presenilin 1 and 2 have been found to be the catalytic components of γ-secretase. Secretases belong to the family of intramembrane-cleaving proteases (i-CLiPs), whose members are Enzymatic cleavage of substrates within the plane of the lipid bilayer in a process called regulated intramembrane proteolysis. (Brown et al., 2000, Cell 100, 391-398; Kopan and Ilagan, 2004, Nat. Rev. Mol. Cell Biol. 5, 499-504). γ-secretase cleaves multiple substrates, including APP. Specifically, APP is first cleaved by β-secretase, This leads to soluble APPβ (sAPPβ) and the carboxyl-terminal fragment of APP (CTF). CTF is further converted to γ-selenium. It is cleaved by cretase to generate Aβ and the intracellular domain of APP (AICD). Tissue-mediated cleavage occurs at various sites, resulting in the production of different species of Aβ, including Aβ40 and Aβ42. (Zhang et al., 2011, Mol. Brain 4, 3).

[0036] Defects in PS-1 or PS-2 affect the activity of γ-secretase and therefore Aβ peptide synthesis. This alters the production of β-adipeptides, altering the relative amounts of Aβ42 versus Aβ40 (Haas et al., 2012, Cold Spring Harbor Laboratory, New York, 1999). ng Harb Perspect Med. 2(5): a006270). The production and accumulation of Aβ initiates a cascade of neurodegenerative events. This induces the formation of senile plaques and intraneuronal fibrils in various diseases and disorders such as AD. This leads to tangles and neuronal loss (Greenfield et al., 2000, Front. Biosci. 5, D 72-D83; see Golde, 2005, Brain Pathol. 15, 84-87).

[0037] In addition to APP, γ-secretase also mediates, among other things, the synthesis of many other type I transmembrane proteins. Proteins: Notch (see De Strooper et al., 1999, Nature 398, 518-522), E-cadherin (Mara mbaud et al., 2002, EMBO J. 21, 1948-1956), ErbB4 (Ni et al., 2001, Scienc e 294, 2179-2181), CD44 (Lammich et al., 2002, J. Biol. Chem. 277, 44754-44 759), tyrosinase (Wang et al., 2006, Proc. Natl. Acad. Sci. USA 103, 353 -358), TREM2 (Wunderlich et al., 2013, J. Biol. Chem. 288, 33027-33036) and alcadein (Hata et al., 2012, Mol. Neurodegener. 7:16. 10.1186 / 1750-1326- 7-16), implicating γ-secretase in a wide range of biological activities. (See Zhang et al., 2014, Front Cell Neurosci. 8, 427.) Thus, γ -Drugs designed to target secretases have not shown sufficient promise in clinical trials. For example, the γ-secretase inhibitor (GSI) semagasesta In a Phase III clinical trial of the drug, it did not affect cognitive improvement and patients receiving high doses The patients had significantly worse functional abilities. It also led to more adverse events, including skin cancer and infections. (Doody et al., 2013, N. Engl. J. Med. 369, 341-350). BMS-708,163 from Isotol-Myers-Squibb (BMS) (Gillman et al., 2010, ACS Med Chem Lett 1: 120-124), and Pfizer's PF-3,084,014 (Lanz et al., 2010, J Pharmacol Exp Ther. r 334: 269-277; De Strooper et al., 2012, Cold Spring Harb Perspect Med. 2(1): A new class of γ-secretors selectively binds to APP while sparing Notch, such as a006304. Even with taurate inhibitors, no progress has been made in terms of further clinical trials. Subsequently, after the failure of GSI, the industry shifted to the development of γ-secretase modulators (GSMs). First generation GSMs showed low efficacy and unfavorable neuropharmacokinetic properties (Zhang et al., 2014, Front Cell Neurosci. 8, 427). It is the only second-generation GSM in clinical development. E2012 has not had an update from its sponsor, Eisai Medical Research, since 2008. Therefore, we were able to inhibit the interaction between γ-secretase and βAPP without affecting other substrates. There remains a need for new therapeutic agents that can specifically interfere.

[0038] As demonstrated in Section 6 below, in certain embodiments, the peptides provided herein comprise: It competitively occupies the enzyme binding site on βAPP, preventing the binding of γ-secretase to βAPP. The peptides provided herein target the substrate βA instead of the enzyme γ-secretase. Binding to PP gives the peptide unparalleled specificity and an excellent efficacy and safety profile. The peptides provided herein are highly likely to be transformed into a β40 inhibitor. (e.g., after a single subcutaneous administration for 24 hours, 8M2D was shown to have a long-lasting effect on Aβ40 reduction of approximately 27%. The peptides provided herein also showed a significant effect in fresh human plasma. Relatively stable (e.g., retention was approximately 50%-90% after 24 hours of incubation) In addition, the peptides provided herein were administered to rats via different routes. Because of these and other properties, the compounds provided herein have potent pharmacokinetic exposures. The peptides described herein are useful for treating various Aβ-related diseases or conditions, such as AD. Be a good candidate.

[0039] (5.1 Definition) To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0040] The techniques and procedures described or referenced herein may be easily understood using conventional methodology by those of ordinary skill in the art. It includes those that are generally well understood and / or commonly adopted.

[0041] Unless otherwise defined herein, technical and scientific terms used in the description of the present invention are For purposes of interpreting this specification, the following terms have the meanings commonly understood by those skilled in the art: The explanations of words apply and, whenever appropriate, terms used in the singular also include the plural. and vice versa. In the event of any conflict with this document, the explanations of terms set forth below shall take precedence.

[0042] The terms "polypeptide" and "peptide" and "protein" are used interchangeably herein. It is used generically to refer to a polymer of amino acids of any length. A polymer can be linear or branched. It may be branched, it may contain modified amino acids and it may be interrupted by non-amino acids. The term also refers to amino acid polymers that are modified, either naturally or by intervention; e.g., disulfides. The peptide may be modified by peptide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also, for example, amino acids, including but not limited to unnatural amino acids, can be used. Polypeptides containing one or more analogs of amino acids, as well as other modifications known in the art, are defined. It is included within the meaning.

[0043] The terms "bind" or "binding" refer to interactions between molecules, including, for example, forming a complex. The interaction may be, for example, hydrogen bonding, ionic bonding, hydrophobic interactions, and / or The interactions may be non-covalent, including van der Waals interactions. The bond or association of two or more molecules that are held together by a noncovalent bond, interaction, or force The strength of the total non-covalent interactions between two peptides can be determined by the strength of the total non-covalent interactions between one peptide and the other peptide. The affinity of a peptide to another peptide. The ratio of the dissociation rates (koff) of the enzymes (k / kon) is the dissociation constant KD, which is inversely proportional to the affinity. The lower the dissociation constant of the peptides provided herein for their targets, the higher the affinity. The KD may be prepared by any of the methods provided herein or any other method known to one of skill in the art. The determination can be made using the

[0044] The term "variant" when used in reference to a peptide refers to a peptide that is different from the native or unmodified sequence. In comparison, a peptide containing one or more (e.g., about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions The term "variant" as used herein may refer to a peptide or polypeptide. The "modification" of an amino acid residue / position in the starting sequence includes the "modification" of an amino acid residue / position in the starting sequence. Refers to major amino acid sequence changes compared to the amino acid sequence, and the amino acid residue / position is Variations arise from alterations in the sequence, including the replacement of a residue with another amino acid. Substitutions (e.g., conservative or non-conservative substitutions) or their isomeric forms, the chemistry of amino acid residues Alterations, such as modifications to one or more (e.g., typically fewer than 5, 4, or 3) adjacent residues / positions ) amino acid insertions and / or deletions of said residues / positions.

[0045] The terms "identity" or "homology" refer to sequences as determined by aligning and comparing sequences. As used herein, a reference polypeptide refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules. With respect to peptide sequences, "percent (%) amino acid sequence identity" is, where appropriate, the maximum percent To achieve uniform sequence identity, the reference polymorphisms are aligned and gaps are introduced. Defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a peptide sequence and does not take into account any conservative substitutions as part of the sequence identity. Alignment for purposes of determining identity can be performed using, for example, BLAST, BLAST-2, ALIGN, or M Using publicly available computer software such as EGALIGN (DNAStar) software This can be accomplished in a variety of ways within the purview of one skilled in the art. Alignment analysis, including the algorithm required to achieve maximal alignment over the entire length of the string. Appropriate parameters for aligning the columns can be determined.

[0046] As used herein, the term "Fc region" refers to, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. It is used to define the C-terminal region of an immunoglobulin heavy chain that contains the Fc region. Although the boundaries of the Fc region of a globulin heavy chain may vary, the human IgG heavy chain Fc region has the following structure: The term "Cys226" or "Pro230" refers to a sequence extending from the amino acid residue at position 226 to the carboxyl terminus of the corresponding amino acid. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) is responsible for, e.g., the production of antibodies. or removed during purification or by recombinantly engineering the nucleic acid encoding the heavy chain of the antibody. Therefore, the composition of the intact antibodies can be determined by a population of antibodies in which all the K447 residues have been removed, K4 A population of antibodies in which the 47 residue had not been removed, and a mixture of antibodies with and without the K447 residue A "functional Fc region" may include an antibody population that has an "effector function" of a native sequence Fc region. Exemplary "effector functions" include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis. downregulation of cell surface receptors (e.g., B cell receptors). The receptor function is generally defined as the Fc region being a binding region or domain (e.g., an antibody variable region or domain) and evaluated using a variety of assays known to those of skill in the art. A "variant Fc region" can have at least one amino acid modification (e.g., The amino acid sequence of the native Fc region is different from that of the native Fc region by substitution, addition, or deletion. In one embodiment, the variant Fc region comprises a native sequence Fc region or an Fc region of a parent polypeptide. At least one amino acid substitution compared to the native sequence Fc region or parent polypeptide. The peptide has about 1 to about 10 amino acid substitutions, or about 1 to about 5 amino acid substitutions in the Fc region. As used herein, a variant Fc region is a variant Fc region that is a native sequence Fc region and / or a parent polypeptide. or at least about 90% homology thereto, e.g., It may have at least about 95% homology therewith.

[0047] The term "vector" refers to a vector used to introduce a nucleic acid sequence into a host cell, e.g., as provided herein. carrying a nucleic acid sequence comprising a nucleic acid sequence encoding the peptide to be synthesized or a parent peptide thereof; Vectors that can be used include, for example, expression vectors. -, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes. and a selection sequence or marker operable for stable integration into the host cell chromosome. In addition, the vector may contain one or more selectable marker genes and appropriate expression control genes. Selectable marker genes that can be included include, for example, antibiotics. It provides nutrients or resistance to toxins, compensates for nutritional deficiencies, or provides important nutrients not contained in the medium. The expression control sequences include constitutive and inducible promoters well known in the art. The nucleic acid molecule may include a promoter, a transcription enhancer, a transcription terminator, etc. When co-expressed, both nucleic acid molecules can be expressed, for example, in a single expression vector or in separate expression vectors. For single vector expression, the coding nucleic acids can be inserted into one common expression vector. operably linked to the regulatory sequences, or one inducible promoter and one constitutive promoter. The nucleic acid molecule can be linked to a different expression control sequence, such as a promoter. can be confirmed using methods well known in the art. Such methods include, for example, Nucleic acid analysis, such as Northern blots or polymerase chain reaction (PCR) amplification of mRNA; Immunoblotting for expression of the product or nucleic acid sequence to be introduced or its corresponding Those skilled in the art will appreciate that the present invention encompasses any suitable assay for testing the expression of a gene product associated with a nucleic acid molecule. It is understood that the vector is expressed in sufficient amounts to produce the desired product, and further, that the vector is capable of expressing the desired product in sufficient amounts to produce the desired product. It is understood that expression levels can be optimized to obtain sufficient expression using well known methods.

[0048] As used herein, the term "host" refers to an animal, such as a mammal (eg, a human).

[0049] As used herein, the term "host cell" refers to a particular host cell that can be transfected with a nucleic acid molecule. The progeny of such a cell includes, but is not limited to, the subject cell and the progeny or potential progeny of such a cell. Mutations or environmental influences that may occur in successive generations or the incorporation of a nucleic acid molecule into the host cell genome Due to incorporation, the resulting nucleic acid molecule may not be identical to the parent cell transfected with the nucleic acid molecule.

[0050] An "isolated nucleic acid" refers to a nucleic acid sequence that is naturally associated with the native sequence, including other genomic DNA sequences and ribosomal and Nucleic acids that are substantially separated from proteins or complexes such as polymerases, e.g., RNA An "isolated" nucleic acid molecule is a nucleic acid molecule that is present in the natural source of the nucleic acid molecule. It is separated from other nucleic acid molecules. In addition, "isolated" nucleic acid molecules, such as cDNA molecules, When produced by recombinant techniques, the product does not substantially differ from other cellular material or culture medium. or if chemically synthesized, chemical precursors or other chemicals may be used to The term encompasses nucleic acid sequences that have been removed from their natural environment and may not be recombinant. isolated or cloned DNA and chemically synthesized analogs or heterologous systems. A substantially pure molecule includes an isolated form of the molecule. may include.

[0051] "Polynucleotide" or "nucleic acid" are used interchangeably herein and refer to any It refers to a long polymer of nucleotides, including DNA and RNA. A nucleotide is a deoxyribonucleic acid. Polynucleotides, ribonucleotides, modified nucleotides or bases, and / or or can be incorporated into a polymer by DNA or RNA polymerase or synthetic reactions. The polynucleotide may be any material capable of carrying out the above-mentioned steps. As used herein, "oligonucleotide" refers to a nucleic acid that is ... is generally, but not necessarily, less than about 200 nucleotides in length. Generally refers to a single-stranded synthetic polynucleotide. The terms "oligonucleotide" and "polynucleotide" are used interchangeably. The above description of polynucleotides includes oligonucleotides and nucleotides. It is equally and fully applicable to nucleotides. The left hand end of any single stranded polynucleotide sequence shown is the 5' end. The left side of the nucleotide sequence is called the 5' direction. The direction of addition of 5' to 3' of the nascent RNA transcript is called the transcription The 5' end of the RNA transcript is 5' to the 5' end of the RNA transcript. The region of sequence on the DNA strand that is 3' to the 3' end of the RNA transcript is called the "upstream sequence." The region of sequence on the DNA strand that has the same sequence as the RNA transcript is referred to as the "downstream sequence."

[0052] As used herein, the term "pharmaceutical acceptable" means any compound that is approved by a federal or state regulatory agency. or approved by the United States Pharmacopoeia, the European Pharmacopoeia, or Animal, and more specifically means it is listed in another generally recognized pharmacopoeia for human use do.

[0053] An "excipient" is a substance such as a liquid or solid filler, diluent, solvent, or encapsulating material. An excipient means a medicament, composition, or vehicle that is pharma- ceutically acceptable. Accelerators, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants , emulsifiers, extenders, fillers, flavoring agents, moisturizers, lubricants, fragrances, preservatives, accelerators, release agents, disinfectants Encapsulating materials or additives such as antibacterial agents, sweeteners, solubilizers, humectants and mixtures thereof The term "excipient" also includes diluents, adjuvants (e.g., Freund's adjuvant ( It may refer to a compound (complete or incomplete) or a vehicle.

[0054] In some embodiments, the excipient is a pharma- ceutically acceptable excipient. Examples of acceptable excipients include buffers such as phosphates, citric acid, and other organic acids; aspartic acid, Antioxidants, including corbic acid; low molecular weight (e.g., less than about 10 amino acid residues) polysaccharides; Peptides; proteins such as serum albumin, gelatin, or immunoglobulins; polyvinyl Hydrophilic polymers such as pyrrolidone; glycine, glutamine, asparagine, arginine, or amino acids such as lysine; monosaccharides including glucose, mannose, or dextrin , disaccharides, and other carbohydrates; chelating agents such as EDTA; mannitol and sorbitol, etc. salt-forming counterions such as sodium; and / or TWEEN®, polyethylene glycol, Examples of suitable surfactants include ethylene glycol (PEG), and non-ionic surfactants such as PLURONICS™. Other examples of pharma- ceutically acceptable excipients are found in Remington and Gennaro, Remington's Pharmacology, The method is described in Remington's Pharmaceutical Sciences (18th ed. 1990).

[0055] In one embodiment, each component is compatible with the other components of the pharmaceutical formulation and does not cause undue toxicity, irritation, Reasonable benefit / risk without allergic reactions, immunogenicity, or other problems or complications. It means that the product meets the requirements for use in contact with human and animal tissues or organs. "Pharmaceutical Acceptability" (Williams & Wilkinse (eds.), 2005, Pharmaceutical Excipients Handbook) Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al. (eds.), 2009, Handbook of Pharmaceutical Additives, 3rd Edition; Ash and A SH (ed.), 2007, Pharmaceutical Preformulation and Formulation In some embodiments, the pharma- ceutical acceptable excipient is It is not toxic to cells or mammals exposed to it at the dosages and concentrations used. In some embodiments, the pharma- ceutical acceptable excipient is an aqueous pH buffered solution.

[0056] In some embodiments, the excipients are water and oils, peanut oil, soybean oil, mineral oil, gum arabic, glycerin, glycerol ... The composition is preferably a sterile liquid, including oils of petroleum, animal, vegetable, or synthetic origin, such as soybean oil. An exemplary excipient when the (e.g., pharmaceutical composition) is administered intravenously. Liquid and aqueous dextrose and glycerol solutions are commonly used as liquid excipients, particularly for injectable solutions. Excipients include starch, glucose, lactose, sucrose, Gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerin Rolled monostearate, talc, sodium chloride, dried skim milk, glycerol, The composition may also contain propylene, glycol, water, ethanol, etc. Optionally, the composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. , solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. The oral composition containing the formulation may be in the form of pharmaceutical grade mannitol, lactose, or glycerol. Starch, Magnesium stearate, Sodium saccharin, Cellulose, Carbonate Standard excipients such as magnesium may be included.

[0057] The composition containing the pharmaceutical peptide may be, for example, isolated or purified, together with an appropriate amount of an excipient. The peptide may be in the form of

[0058] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to produce a desired result. It refers to an amount of a peptide or pharmaceutical composition provided herein that is sufficient.

[0059] The terms "subject" and "patient" may be used interchangeably. In embodiments, the subject is a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or a primate. (e.g., monkeys and humans). In a specific embodiment, the subject is a human. In one embodiment, the subject is a mammal, e.g., a human, who has been diagnosed with a condition or disorder. In another embodiment, the subject is a mammal at risk of developing a condition or disorder, e.g. Well, a human.

[0060] "Administer" or "administration" refers to the delivery of a substance present outside the body via mucosa, intradermal, intravenous, or intramuscular route. and / or any other method of physical delivery described herein or known in the art. "Injection" refers to the act of injecting or otherwise physically delivering a therapeutic agent to a patient by any method or method.

[0061] As used herein, the terms "treat," "treatment," and "treating" refer to one or more therapeutic A reduction in the progression, severity, and / or duration of a disease or condition resulting from the administration of a therapeutic agent; or Treating refers to improving the condition even though the patient may still be suffering from the underlying condition. One or more symptoms associated with the underlying disease such that the patient nevertheless experiences improvement This may be determined by assessing whether there has been a reduction, mitigation and / or mitigation of The term "treating" includes both disease management and amelioration. "Management" and "management" do not necessarily result in a cure of the disease in a subject. Refers to the beneficial effects resulting from a treatment.

[0062] The terms "prevent", "preventing" and "prevention" refer to the prevention of a disease, disorder, "Treatment" refers to reducing the likelihood of development (or recurrence) of a disease, condition, or associated symptom(s).

[0063] The terms "alleviate" and "alleviation" refer to a reduction in one or more symptoms of a disorder, disease, or condition (e.g., pain, The term also refers to the alleviation or reduction of side effects associated with an active ingredient. Sometimes, this can refer to a reduction in the level of a disease resulting from a prophylactic or therapeutic agent in a subject. The beneficial effects do not result in a cure of the disorder, disease, or condition.

[0064] The term "contact" or "contacting" refers to any physiological and / or chemical change that occurs as a result of such contact. Contacting is meant to refer to the joining of a therapeutic agent with a cell or tissue such that a therapeutic effect occurs. Therapeutic agents may be produced in vitro, ex vivo, or in vivo. The therapeutic agent is then contacted with cells in a culture medium (in vitro) to determine the effect of the therapeutic agent on the cells. In some embodiments, contacting a cell or tissue with a therapeutic agent provides a therapeutic agent to a subject having the contacted cell or tissue. This includes administration of a therapeutic agent.

[0065] In certain embodiments, the peptides described herein attenuate amyloid-β activity (e.g., In some embodiments, the peptides provided herein In some embodiments, the method described herein reduces amyloid beta activity by at least about 10%. The peptides provided herein attenuate amyloid-β activity by at least about 20%. In some embodiments, the peptides provided herein inhibit amyloid beta activity by at least about 30%. In some embodiments, the peptides provided herein reduce amyloid In some embodiments, the β activity of the agonist provided herein is attenuated by at least about 40%. The peptide attenuates amyloid beta activity by at least about 50%. The peptides provided herein attenuate amyloid-β activity by at least about 60%. In some embodiments, the peptides provided herein reduce amyloid beta activity. In some embodiments, the peptides provided herein attenuate both the agonist and the agonist by about 70%. Attenuates myloid-beta activity by at least about 80%. The peptides provided attenuate amyloid-β activity by at least about 90%. In one embodiment, the peptides provided herein attenuate amyloid beta activity by at least about 95%. In certain embodiments, the compounds described herein inhibit amyloid beta activity at least The attenuation (e.g., partial attenuation) can be between about 15% and about 65%. In one embodiment, the compounds described herein attenuate amyloid beta activity by at least about 30% to about 65%. The signal can be filtered (e.g., partially attenuated).

[0066] In a specific embodiment, the attenuation of amyloid beta activity is assessed by methods known to those of skill in the art. In some embodiments, the attenuation of amyloid beta activity is achieved by administering any of the compounds described herein. This is for amyloid beta activity in the presence of a stimulus that does not include

[0067] A non-limiting example of an amyloid-beta activity is amyloid-beta induced or mediated signaling. Thus, in certain embodiments, the compounds provided herein inhibit amyloid-β induced signaling. Attenuate (e.g., partially attenuate) amyloid-β-induced signaling. Non-limiting examples include glucose transporters, NMDARs, AMPARs, and acetylcholine receptors. activation of inflammatory signaling pathways, including GSK-3, CDK5, PKC, PKA, and Erk1 / 2 receptors, including but not limited to activation of one or more kinases; The activities include blocking ion channels, calcium channels, and calcium phosphate channels. Disruption of umbilical cord homeostasis, mitochondrial oxidative stress, impaired energy metabolism, abnormal glucose These may include neuronal cell death, neuronal cell death, and / or neuronal cell death.

[0068] In some embodiments, the peptides described herein attenuate tau protein activity ( In some embodiments, the peptides provided herein are In some embodiments, the method comprises the steps of: attenuating tau protein activity by at least about 10%; The peptides provided herein attenuate tau protein activity by at least about 20%. In some embodiments, the peptides provided herein reduce tau protein activity. In some embodiments, the peptides provided herein reduce the expression of TA In some embodiments, the method described herein reduces protein activity by at least about 40%. The peptides provided attenuate tau protein activity by at least about 50%. In embodiments, the peptides provided herein inhibit tau protein activity by at least about 60%. In some embodiments, the peptides provided herein attenuate tau protein by %. In some embodiments, the method of the present invention provides a method for the treatment of a pulmonary artery disease comprising administering to a patient a therapeutically effective amount of ... pulmonary artery disease (PAS) provided herein. The peptide attenuates tau protein activity by at least about 80%. In this regard, the peptides provided herein attenuate tau protein activity by at least about 90%. In some embodiments, the peptides provided herein inhibit tau protein activity. In certain embodiments, the compounds described herein attenuate tauta by at least about 95%. It is possible to attenuate (e.g., partially attenuate) a protein by at least about 15% to about 65%. In certain embodiments, the compounds described herein can inhibit tau protein by at least about 30 % to about 65% attenuated (e.g., partially attenuated).

[0069] In a specific embodiment, the attenuation of tau protein activity is assessed by methods known to those of skill in the art. In certain embodiments, the attenuation of tau protein activity is measured using a compound described herein. None of this is directed to tau protein activity.

[0070] A non-limiting example of a tau protein activity is tau protein induction or mediated signal transduction. Thus, in certain embodiments, the compounds provided herein are useful for inhibiting tau protein induction. Attenuate (e.g., partially attenuate) signal transduction. Non-limiting effects of tau protein activity Notable examples include interacting with tubulin to stabilize microtubules and formation of tubules and / or straight filaments, activation of inflammatory signaling pathways and One example is impaired insulin signaling in the brain.

[0071] The terms "about" or "approximately" refer to any value that can be determined by one of ordinary skill in the art and that is based in part on the fact that a value is measured or determined. It refers to the allowable error for a particular value that depends on the method used. The terms "about" or "approximately" mean within 1, 2, 3, or 4 standard deviations. The terms "about" and "approximately" mean within 20%, within 15%, within 10% of a given value or range. , less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% means within or below.

[0072] As used herein, the term "amyloid (or amyloid β)-related disease or disorder" refers to ", "Amyloid (or amyloid β)-related disease or disorder," "Amyloid (or amyloid "disease or disorder associated with myocardial infarction (beta myocardial infarction)" or similar term means a disease or disorder characterized by clinical pathological features Abnormal amounts of amyloid beta (Aβ) or monomers, soluble oligomers, insoluble fibrils, and Aβ Any of the different Aβ isoforms, including larger insoluble aggregates such as plaques. The term "Aβ" or "amyloid beta" is used interchangeably herein. Various pathways arise from cleavage of β-APP by γ-secretase outside the intracellular domain of APP(AICD). It refers to any product having a length.

[0073] As used in this disclosure and claims, the singular forms "a," "an," and "the" includes the plural forms unless the context clearly dictates otherwise.

[0074] Wherever embodiments are described herein using the term "comprising," "consisting of" and / or other similar embodiments described in terms of "consisting essentially of" may also be provided. It is understood that embodiments are described herein using the phrase "consisting essentially of." Wherever possible, other similar embodiments described in terms of "consisting of" are also provided. is understood.

[0075] The term "between" used in phrases such as "between A and B" or "between A and B" includes both A and B. Refers to the range.

[0076] As used herein in phrases such as "A and / or B," the term "and / or" refers to both A and B. ; A or B; A (alone); and B (alone). Similarly, "A, B, and / or C" is intended to include The term "and / or" used in phrases such as "and / or" refers to the following embodiments: A, B and C; A, B or C; A or includes each of C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). It is intended to.

[0077] 5.2 Peptides The inventors have identified a sequence of amino acids 66 to 73 of presenilin-1 that has β-APP binding activity. is the same as the [ka] (See SEQ ID NO: 5 in PCT Publication WO 10 / 132609.) By binding to β-APP, the peptide inhibits the binding of full-length native presenilin-1 to β-APP. To prevent the binding of presenilin-1 to β-APP, we aimed to block the biological activity mediated through the binding of presenilin-1 to β-APP. Acts in a dominant-negative manner to inhibit, thereby preventing the formation of Aβ .

[0078] A novel mutant of P8 that unexpectedly exhibits superior stability and / or high efficiency in reducing Aβ levels The peptides provided herein include a C-terminal amino acid sequence. The present invention includes synthetic peptides with partial substitutions of D-amino acids, N-terminal acetylation, and / or D-amino acids. However, this is not limited to the above.

[0079] More specifically, one peptide provided herein (designated 8M1) comprises a C-terminal fragment to SEQ ID NO:1. a sequence containing a terminal amidation (i.e., amidation of the C-terminal amino acid Leu), is the array Asp L -Glu L -Glu L -Glu L -Asp L -Glu L -Glu L -Leu L -CONH2 or [ka] Includes.

[0080] Another peptide provided herein, designated 8M2, has an acetyl group at the N-terminus of SEQ ID NO:2. The peptide comprises an added sequence (i.e., acetylation of the N-terminal amino acid Asp), Column CH3CO-NH-Asp L -Glu L -Glu L -Glu L -Asp L -Glu L -Glu L -Leu L -CONH2 or [ka] Includes.

[0081] Yet another peptide provided herein (designated 8M1D) comprises the first amino acid at the N-terminus of SEQ ID NO:2. The amino acid (i.e., the N-terminal amino acid Asp) is converted to the enantiomer of its D-amino acid, the L-amino acid. and the peptide comprises a sequence substituted with Asp. D -Glu L -Glu L -Glu L -Asp L -Glu L -Gl u L -Leu L -CONH2 or [ka] Contains an array of.

[0082] Yet another peptide provided herein, designated 8M2D, contains an acetyl group at the N-terminus of SEQ ID NO:4. The sequence that adds the aryl group (i.e., the N-terminal amino acid Asp D acetylation of said peptide has the sequence CH3CO-NH-Asp D -Glu L -Glu L -Glu L -Asp L -Glu L -Glu L -Leu L -CONH2 or [ka] Includes.

[0083] In some embodiments, the peptides provided herein inhibit the expression of beta amyloid in cells. Binding of precursor protein (β-APP) to presenilin-1 (PS-1) and / or presenilin-2 (PS-2) Attenuate.

[0084] In some embodiments, the peptides provided herein inhibit the expression of beta-amyloid in cells. β-APP and presenilin-1 (PS-1) and / or presenilin-2 (PS-2) Attenuates (e.g., partially attenuates) the binding of at least about 10%. In one embodiment, the peptides provided herein inhibit the expression of beta amyloid precursor protein in cells. The binding of β-APP to presenilin-1 (PS-1) and / or presenilin-2 (PS-2) is In some embodiments, the peptides provided herein reduce intracellular Beta-amyloid precursor protein (β-APP) and presenilin-1 (PS-1) and / or presenilin-2 (PS-3) in In some embodiments, the present invention reduces the binding of senilin-2 (PS-2) by at least about 30%. The peptides provided herein bind to the beta-amyloid precursor protein (β-APP) in cells. Attenuating the binding of presenilin-1 (PS-1) and / or presenilin-2 (PS-2) by at least about 40%. In some embodiments, the peptides provided herein inhibit the beta-amyloid endothelial cell proliferation and / or cell death. Myloid precursor protein (β-APP) and presenilin-1 (PS-1) and / or presenilin-2 (PS -2) by at least about 50%. The peptides involved in the synthesis of beta-amyloid precursor protein (β-APP) and presenilin The antibody reduces the binding of presenilin-1 (PS-1) and / or presenilin-2 (PS-2) by at least about 60%. In some embodiments, the peptides provided herein inhibit the expression of beta amyloid precursors in cells. The binding of the cellular protein (β-APP) to presenilin-1 (PS-1) and / or presenilin-2 (PS-2) was Attenuates by at least about 70%. In some embodiments, the peptides provided herein The β-amyloid precursor protein (β-APP) and presenilin-1 (PS-1) in cells and / or attenuates binding of presenilin-2 (PS-2) by at least about 80%. In the present specification, the peptides provided herein are capable of inhibiting the beta amyloid precursor protein (AAP) in cells. The binding of (β-APP) to presenilin-1 (PS-1) and / or presenilin-2 (PS-2) is at least about 9 In some embodiments, the peptides provided herein are capable of reducing the expression of IL-1 in cells by 0%. beta-amyloid precursor protein (β-APP) and presenilin-1 (PS-1) and / or presenilin-2 (PS-3) in the It attenuates the binding of PS-2 by at least about 95%.

[0085] In some embodiments, the peptides provided herein inhibit amyloid beta (Aβ) expression in cells. In some embodiments, the production of The peptides provided in the present invention attenuate Aβ production in cells by at least about 10%. In some embodiments, the peptides provided herein inhibit at least the production of Aβ in a cell. In some embodiments, the peptides provided herein also reduce the expression of cellular In some embodiments, the method described herein reduces Aβ production in the rat by at least about 30%. The provided peptides attenuate Aβ production in cells by at least about 40%. In some embodiments, the peptides provided herein inhibit the production of Aβ in cells. In some embodiments, the peptides provided herein reduce intracellular In some embodiments, the method provides for the treatment of Aβ by attenuating Aβ production in a subject by at least about 60%. The peptides provided attenuate Aβ production in cells by at least about 70%. In embodiments, the peptides provided herein inhibit the production of Aβ in cells by at least about 8 In some embodiments, the peptides provided herein are capable of reducing the expression of IL-1 in cells by 0%. In some embodiments, the compositions provided herein attenuate the production of Aβ by at least about 90%. The peptides described herein attenuate Aβ production in cells by at least about 95%.

[0086] In some embodiments, the peptides provided herein are used to treat or reduce amyloid beta (Aβ) in a subject. In some embodiments, the method of the present invention attenuates (e.g., partially attenuates) the production of The peptides provided herein attenuate the amount of Aβ in the plasma of a subject by at least about 10%. In some embodiments, the peptides provided herein reduce the amount of Aβ in the plasma of a subject. In some embodiments, the peptides provided herein reduce the expression of In some embodiments, the amount of Aβ in the plasma of the subject is attenuated by at least about 30%. The peptides provided herein attenuate the amount of Aβ in the plasma of a subject by at least about 40%. In some embodiments, the peptides provided herein are used to reduce the amount of Aβ in the plasma of a subject. In some embodiments, the peptides provided herein attenuate the expression level of In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of Aβ in the plasma of the subject by at least about 60%. The peptides provided herein are capable of attenuating the amount of Aβ in the plasma of a subject by at least about 70%. In some embodiments, the peptides provided herein are capable of inhibiting Aβ in the plasma of a subject. In some embodiments, the amount of The peptide attenuates the amount of Aβ in the plasma of the subject by at least about 90%. In this regard, the peptides provided herein are capable of reducing the amount of Aβ in the plasma of a subject by at least about 95%. To weaken.

[0087] In some embodiments, the peptides provided herein reduce the amount of Aβ in the CSF of a subject. Attenuates by at least about 10%. In some embodiments, the peptides provided herein attenuates the amount of Aβ in the CSF of the subject by at least about 20%. The peptides provided herein attenuate the amount of Aβ in the CSF of a subject by at least about 30%. In some embodiments, the peptides provided herein enhance the expression of IL-1 in the CSF of a subject. In some embodiments, the method provides a method for treating Aβ-related disorders comprising administering a therapeutically effective amount of the ... The peptides used in the present invention reduce the amount of Aβ in the CSF of a subject by at least about 50%. In embodiments, the peptides provided herein reduce the amount of Aβ in the CSF of a subject. In some embodiments, the peptides provided herein also reduce the expression of a target In some embodiments, the method of the present invention reduces the amount of Aβ in the CSF of a patient by at least about 70%. The peptides provided herein attenuate the amount of Aβ in the CSF of a subject by at least about 80%. In some embodiments, the peptides provided herein are intended to assess the amount of Aβ in the CSF of a subject. In some embodiments, the peptides provided herein attenuate the expression level of The method of the present invention provides a method for treating CSF disorders in a subject, comprising administering to the subject at least about 95% of Aβ.

[0088] In certain embodiments, the peptides described herein attenuate amyloid-β activity (e.g., Non-limiting examples of amyloid beta activity include amyloid beta induction or is a signal transduction mediator. Therefore, in some embodiments, the peptides provided herein The amyloid-β inhibitors attenuate (e.g., partially attenuate) amyloid-β-induced signaling. Another non-limiting example of loid beta induced signaling is the glucose transporter, NMDAR. , AMPAR and acetylcholine receptors, activation of inflammatory signaling pathways, and GSK-3, CD Activation of one or more kinases, including but not limited to K5, PKC, PKA, and Erk1 / 2. Activities include, but are not limited to, interaction (including blocking) with the receptor. Blockade of ion channels, disruption of calcium homeostasis, mitochondrial oxidative stress, and energy These may include impaired glucose metabolism, abnormal glucose regulation and / or neuronal cell death.

[0089] In some embodiments, the peptides provided herein inhibit amyloid beta activity in cells. Attenuate the activity (e.g., amyloid-β induced signaling) by at least about 10%. In embodiments, the peptides provided herein inhibit amyloid beta activity in cells (e.g., In some embodiments, the amyloid β-induced signaling is attenuated by at least about 20%. The peptides provided herein inhibit intracellular amyloid beta activity (e.g., amyloid In some embodiments, the method of the present invention attenuates β-induced signaling by at least about 30%. The peptides provided herein inhibit amyloid-β activity in cells (e.g., amyloid-β-induced sigma). In some embodiments, the method provides a method for reducing the amount of cytotoxicity (null transmission) of a cytotoxic agent provided herein by at least about 40%. The peptides that are produced inhibit Aβ activity (e.g., Aβ-induced signaling) in cells. Attenuates by at least about 50%. In some embodiments, the peptides provided herein inhibits Aβ activity (e.g., Aβ-induced signaling) in cells by at least about In some embodiments, the peptides provided herein attenuate the expression of the IL-1 protein in cells by 60%. Attenuate Aβ activity (e.g., Aβ-induced signaling) by at least about 70% In some embodiments, the peptides provided herein inhibit intracellular amyloid beta. Attenuates activity (e.g., amyloid-β-induced signaling) by at least about 80%. In embodiments, the peptides provided herein inhibit intracellular amyloid beta activity (e.g., , amyloid-β induced signaling) by at least about 90%. In this regard, the peptides provided herein are intended to suppress intracellular amyloid beta activity (e.g., amyloid The antibody attenuates β-induced signal transduction by at least about 95%.

[0090] In some embodiments, the peptides provided herein are used to treat amyloidosis in a subject. Attenuates amyloid beta activity (e.g., amyloid beta-induced signaling) by at least about 10%. In some embodiments, the peptides provided herein are used to reduce amyloid beta activity ( For example, it attenuates amyloid-β-induced signaling by at least about 20%. In embodiments, the peptides provided herein are used to reduce amyloid beta activity (e.g., , amyloid-β induced signaling) by at least about 30%. In this regard, the peptides provided herein are intended to reduce amyloid beta activity (e.g., amyloid β activity) in a subject. In some embodiments, the method attenuates IL-6 induced signaling by at least about 40%. The peptides provided herein are intended to reduce amyloid beta activity (e.g., amyloid In some embodiments, the method of the present invention attenuates β-induced signaling by at least about 50%. The peptides provided herein are intended to be used to inhibit amyloid beta activity (e.g., amyloid beta induction) in a subject. In some embodiments, the method of the present invention provides a method for reducing the amount of signal transduction that occurs during cell death by at least about 60%. The peptide provided may be used to inhibit amyloid beta activity (e.g., amyloid beta-induced signaling) in a subject. In some embodiments, the method provided herein attenuates the transmission of radiation (radiation) by at least about 70%. The peptide can be used to inhibit amyloid-beta activity (e.g., amyloid-beta induced signaling) in a subject. In some embodiments, the peptides provided herein attenuate the expression level of The method comprises the steps of: reducing amyloid-beta activity (e.g., amyloid-beta induced signaling) in a subject; In some embodiments, the peptides provided herein attenuate both the and reducing amyloid-β activity (e.g., amyloid-β-induced signaling) in the elephant by at least about 95%. % attenuation.

[0091] In certain embodiments, the peptides provided herein are useful for inhibiting the production of tau protein in cells. In some embodiments, the method as provided herein attenuates (e.g., partially attenuates) The peptides used in the present invention attenuate the production of tau in cells by at least about 10%. In one embodiment, the peptides provided herein reduce the production of tau in cells by at least about 20%. In some embodiments, the peptides provided herein inhibit the expression of tau in cells. In some embodiments, the peptides provided herein attenuate production by at least about 30%. In some embodiments, the peptide attenuates the production of tau in a cell by at least about 40%. The peptides provided herein attenuate intracellular tau production by at least about 50%. In some embodiments, the peptides provided herein reduce the production of tau in cells. In some embodiments, the peptides provided herein attenuate the expression level of In some embodiments, the method of the present invention reduces intracellular tau production by at least about 70%. The peptides provided herein attenuate the production of tau in cells by at least about 80%. In some embodiments, the peptides provided herein inhibit the production of tau in cells at least In some embodiments, the peptides provided herein attenuate intracellular attenuates tau production by at least about 95%.

[0092] In certain embodiments, the peptides provided herein attenuate the production of tau in a subject. In some embodiments, the method provided herein The peptide reduces the amount of tau in the plasma of the subject by at least about 10%. In some embodiments, the peptides provided herein reduce the amount of tau in the plasma of a subject by at least about 20%. In some embodiments, the peptides provided herein attenuate the plasma concentration of In some embodiments, the method provides a method for treating tau-related disorders comprising administering to a subject a therapeutically effective amount of tau to a subject, the method comprising administering to a subject a therapeutically effective amount of tau to a subject, the subject a therapeutically effective amount of tau to a subject The peptide reduces the amount of tau in the plasma of a subject by at least about 40%. In embodiments, the peptides provided herein reduce the amount of tau in the plasma of a subject by at least about In some embodiments, the peptides provided herein are administered to a subject in the blood. In some embodiments, the method provides for the treatment of a pulmonary edema by at least about 60%. The provided peptides attenuate the amount of tau in the plasma of a subject by at least about 70%. In embodiments, the peptides provided herein attenuate the amount of tau in the plasma of a subject. In some embodiments, the peptides provided herein also reduce the expression of a target In some embodiments, the method of the present invention provides a method for reducing the amount of tau in plasma of a subject by at least about 90%. The peptides provided in attenuate the amount of tau in the plasma of a subject by at least about 95%.

[0093] In some embodiments, the peptides described herein attenuate tau protein activity ( A non-limiting example of a tau protein activity is Induction or mediation of signal transduction. Thus, in one embodiment, The peptide attenuates (e.g., partially attenuates) tau protein-induced signaling A non-limiting example of a tau protein activity is the interaction of tau with tubules to stabilize microtubules. Interacting with brin, forming helices and / or straight filaments, flame These include activation of pathological signaling pathways and impaired insulin signaling in the brain.

[0094] In some embodiments, the peptides provided herein inhibit tau protein in cells. Attenuates activity (e.g., tau protein-induced signaling) by at least about 10%. In some embodiments, the peptides provided herein inhibit tau protein activity in cells (e.g., For example, it attenuates tau protein-induced signaling by at least about 20%. In embodiments, the peptides provided herein inhibit tau protein activity in cells (e.g., In some embodiments, the tau protein-induced signal transduction is attenuated by at least about 30%. In this regard, the peptides provided herein are intended to inhibit tau protein activity in cells (e.g., tauta In some embodiments, the method further comprises attenuating expression of the IL-1 protein by at least about 40%. The peptides provided herein are useful for inhibiting tau protein activity in cells (e.g., tau protein activation). In some embodiments, the present invention attenuates the expression of a phosphodiesterase (PDS)-induced signaling by at least about 50%. The peptides provided herein are intended to inhibit tau protein activity in cells (e.g., tau protein induction). In some embodiments, the method of the present invention provides a method for reducing the amount of signal transduction that occurs during cell death by at least about 60%. The peptides provided may be used to inhibit tau protein activity in cells (e.g., tau protein-induced signal transduction). In some embodiments, the method provided herein attenuates the transmission of radiation (radiation) by at least about 70%. The peptides inhibit tau protein activity in cells (e.g., tau protein-induced signal transduction). In some embodiments, the peptides provided herein attenuate the expression level of The drug reduces tau protein activity (e.g., tau protein-induced signaling) in cells. In some embodiments, the peptides provided herein reduce the expression of cellular Inhibits intracellular tau protein activity (e.g., tau protein-induced signal transduction) by at least about 95%. % attenuation.

[0095] In some embodiments, the peptides provided herein are useful for detecting tau protein in a subject. Attenuates protein activity (e.g., tau protein-induced signal transduction) by at least about 10%. In some embodiments, the peptides provided herein are used to detect and / or treat tau protein in a subject. Attenuates activity (e.g., tau protein-induced signaling) by at least about 20%. In some embodiments, the peptides provided herein are useful for evaluating tau protein activity in a subject. (e.g., tau protein-induced signaling) by at least about 30%. In embodiments, the peptides provided herein are useful for measuring tau protein activity (e.g., For example, it attenuates tau protein-induced signaling by at least about 40%. In embodiments, the peptides provided herein are used to reduce tau protein activity (e.g., For example, the tau protein-induced signal transduction is attenuated by at least about 50%. In one embodiment, the peptides provided herein are used to reduce tau protein activity (e.g., , tau protein-induced signaling) by at least about 60%. In some embodiments, the peptides provided herein are used to treat tau protein activity (e.g., In some embodiments, the tau protein-induced signal transduction is attenuated by at least about 70%. Thus, the peptides provided herein are useful for reducing tau protein activity (e.g., tau expression) in a subject. In some embodiments, the antibody or antibody that inhibits the expression of the IL-1 protein is attenuated by at least about 80%. The peptides provided herein are useful for reducing tau protein activity (e.g., tau In some embodiments, the IL-1 protein-induced signal transduction is attenuated by at least about 90%. The peptides provided herein can be used to measure tau protein activity (e.g., tauta The antibody attenuates the expression of β-lactamase (β-lactamase) by at least about 95%.

[0096] In some embodiments, the peptides provided herein are variants of the above-mentioned peptides. Includes.

[0097] In some embodiments, modifications (including but not limited to) of the amino acid sequences of the peptides provided herein For example, thermostability, expression levels, glycosylation, and / or immunogenicity are contemplated. Altering or improving certain biological properties of the peptide, including, but not limited to, decreasing Therefore, in addition to the peptides described herein, peptide variants may be used. It is contemplated that variants can be prepared. For example, peptide variants can be prepared by modifying the structure of the parent peptide. and / or by introducing appropriate nucleotide changes into the coding DNA for the desired peptide. It can be prepared by synthesis of

[0098] The alteration may involve the substitution of one or more codons encoding the parent peptide, resulting in a change in the amino acid sequence. The amino acid substitutions may be substitutions, deletions, or insertions, such as replacement of serine with leucine. Replacement of one amino acid with another having similar structural and / or chemical properties, e.g. For example, this may be the result of conservative amino acid substitutions. Standard techniques known to those skilled in the art can be used to For example, the present invention provides methods for the preparation of nucleotide sequences, including site-directed mutagenesis and PCR-mediated mutagenesis that result in amino acid substitutions. The present invention may be used to introduce mutations into the nucleotide sequences encoding the molecules provided herein. The substitution, insertion or deletion can be anywhere within the range of about 1 to 5 amino acids. In certain embodiments, the substitutions, deletions, or insertions are fewer than 10 amino acid substitutions, 5 less than four amino acid substitutions, less than three amino acid substitutions, or less than two amino acid substitutions In a specific embodiment, the substitutions are at one or more predicted non-essential amino acid residues. Conservative amino acid substitutions are made in the sequence. Permitted changes include insertions, deletions, or deletions of amino acids in the sequence. Systematically perform deletions or substitutions and identify the resulting mutants as represented by the full-length or mature native sequence. The activity of the compound can be determined by testing for activity against the compound.

[0099] A "conservative amino acid substitution" is one in which the amino acid residue has a side chain with a similar charge. A substitution is a substitution in which a phosphodiesterase is replaced with a phosphodiesterase residue. These families include those that contain basic side chains (e.g. , lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid ), polar uncharged side chains (e.g., glycine, asparagine, glutamine, serine, threonine , tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine syn, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g. threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenyl It also contains amino acids with the following mutations: alanine, tryptophan, histidine. can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis. The resulting mutants can be screened for biological activity to identify mutants that retain activity. After mutagenesis, the encoded protein can be expressed. and the activity of the protein can be determined.

[0100] Amino acids are classified according to the characteristics of their side chains: (1) Nonpolar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P) , Phe (F), Trp (W), Met (M); (2) Uncharged polarity: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic: Asp (D), Glu (E); and (4) basic: Lys (K), Arg (R), His(H) similarity (Lehninger, Biochemistry 73- 75 (2nd ed. 1975). Alternatively, naturally occurring residues share common side chain properties: (1) hydrophobicity: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; ( (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pr o; and (6) aromatic: can be divided into groups based on Trp, Tyr, Phe.

[0101] In one embodiment, the peptides provided herein are those peptides described in the Examples section below. At least 70%, at least 75%, at least 80%, at least 85%, It comprises an amino acid sequence that is at least 90%, at least 95%, or at least 99% identical.

[0102] The modifications were made using oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and This can be done using methods known in the art, such as PCR mutagenesis. Induction (Carter, 1986, Biochem J. 237:1-7; and Zoller et al., 1982, Nucl. Acid Res. 10:6487-500), cassette mutagenesis (Wells et al., 1985, Gene 34:315-23), (see references), or other known techniques can be used to generate DNA variants of the parent peptide. The procedure can be performed on modified DNA.

[0103] An oligomer or fusion polypeptide comprising the peptides provided herein is provided in accordance with the present disclosure. In some embodiments, the oligomer comprises a peptide as provided herein. An oligomer may be a covalent bond including a dimer, trimer, or higher oligomer. In some embodiments, the oligomer may be in the form of a non-covalently linked multimer. maintains the binding capacity of the polypeptide component and thus provides bivalent, trivalent, etc. binding sites In some embodiments, the present disclosure provides covalent linkages between peptide moieties fused to a polypeptide. The peptides provided herein are linked via covalent or non-covalent interactions. Such peptides are directed to oligomers and have the property of promoting oligomerization.

[0104] The present disclosure also provides peptides of the present disclosure covalently attached to one or more agents by synthetic linkers. The present invention provides a conjugate comprising any one of the following:

[0105] In some embodiments, the peptides provided herein are intended to be used in combination with, for example, another therapeutic agent (e.g. for example, a cytotoxic agent) or a diagnostic or detectable molecule; Conjugated or recombinantly fused peptides can be, for example, For example, the conjugated polypeptide may be useful for treating or preventing a disease or disorder. or a recombinant fused peptide, for example, for preventing or inhibiting the initiation, development, progression, or progression of a disease or disorder. and / or may be useful in monitoring the severity or prognosis.

[0106] Such diagnosis and detection include, but are not limited to, horseradish peroxidase, Alkaline phosphatase, beta-galactosidase, or acetylcholinesterase Any of a variety of enzymes; including but not limited to streptavidin / biotin or avidin / biotin Prosthetic groups such as; but not limited to, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, chloride fluorescent materials such as dansyl, or phycoerythrin; luminescent materials such as, but not limited to, luminol; Optical materials; bioactivities such as, but not limited to, luciferase, luciferin, or aequorin; Optical materials; chemiluminescent materials, such as, but not limited to, acridinium-based compounds or HALOTAG; However, iodine (131I, 125I, 123I, and 121I), carbon (14C), sulfur (35S), and tritium (3H), indium (115In, 113In, 112In, and 111In), technetium (99Tc), thallium (2 01Ti), Gallium (68Ga and 67Ga), Palladium (103Pd), Molybdenum (99Mo), Xenon (133 Xe), Fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 18 6Re, 188Re, 142Pr, 105Rh, 97Ru, 68Ge, 57Co, 65Zn, 85Sr, 32P, 153Gd, 169Yb, 51Cr radioactive materials such as 54Mn, 75Se, 113Sn, or 117Sn; and non-radioactive paramagnetic metal ions. This can be achieved by coupling the peptide to a releasable substance.

[0107] To generate a fusion protein, a heterologous protein or polypeptide (or a fragment thereof, For example, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 amino acids. Recombinantly fused or chemically conjugated (covalently or non-covalently conjugated) to the polypeptide Also provided herein are fusion peptides, as well as uses thereof. Fusion proteins containing the provided peptides and heterologous proteins, polypeptides, or peptides In one embodiment, the peptides provided herein are fused to The heterologous protein, polypeptide, or peptide can be used to target the peptide to a particular cell type. It is useful for targeting.

[0108] Immunoglobulin-based oligomers are encompassed by the present disclosure. The peptides provided herein are For many purposes, including increasing the valency of a polypeptide binding site, immunoglobulins may be used. For example, the peptides provided herein can be fused directly or to a molecule such as a phospholipid. It can be fused to the Fc portion of an immunoglobulin via an anchor peptide, and can be used as a can be an IgG molecule, or other isotypes, such as an IgM molecule. An "Fc polypeptide" refers to a polypeptide derived from the Fc region of an antibody that contains any or all of the CH domains of the Fc region. This includes native and mutant forms of the constructed polypeptides.

[0109] Additionally, the peptides provided herein may be used in combination with marker or peptide sequences to facilitate purification. In a specific embodiment, the marker can be fused to a "tag" sequence, such as a marker peptide. Alternatively, the tag amino acid sequence may be provided in, inter alia, a pQE vector (see, e.g., QIAGEN). and hexahistidine peptides such as tags, many of which are commercially available. As described in Gentz ​​et al., 1989, Proc. Natl. Acad. Sci. USA 86:821-24 In addition, hexahistidine provides for convenient purification of the fusion protein. The tag corresponds to an epitope derived from the influenza hemagglutinin protein. Hemagglutinin ("HA") tag (Wilson et al., 1984, Cell 37:767-78), and "FLAG" tag These include, but are not limited to:

[0110] Methods for fusing or conjugating moieties (including polypeptides) to peptides are well known in the art. Fusion proteins are known in the art, for example, gene shuffled, motif shuffled, , exon shuffling, and / or codon shuffling (collectively referred to as "DNA shuffling" The peptides provided herein can be produced through techniques such as recombinant gene expression. Random mutagenesis by run-on PCR, random nucleotide insertion, or other methods The peptides provided herein can be modified by providing A polynucleotide may comprise one or more components, motifs, sections, portions, or domains of one or more heterologous molecules. May be combined with mains, fragments, etc.

[0111] The peptides provided herein may be bound to a solid support, which in particular These solid supports are useful for immunoassays or purification of the partner. Cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or poly These include, but are not limited to, propylene.

[0112] The linker is a "cleavable linker" that facilitates release of the conjugated agent inside the cell. Although cleavable linkers are possible, non-cleavable linkers are also contemplated herein. Linkers for use include, but are not limited to, acid labile linkers (e.g., hydra linkers), disulfide-containing linkers, peptidase-sensitive linkers (e.g., amine valine and / or citrulline, such as citrulline-valine, or phenyl Alanine-lysine-containing peptide linker), photolabile linker, dimethyl linker (Chari et al., 1992, Cancer Res. 52:127-31; and U.S. Patent No. 5,208,020), thioethers, linkers, or hydrophilic phosphorylators designed to circumvent multidrug transporter-mediated resistance (Kovtun et al., 2010, Cancer Res. 70:2528-37).

[0113] Peptide-drug conjugates include BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, Sulfo-EMCS, Sulfo-GMBS, Sulfo-KMUS, Sulfo -MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and SVSB (succinimidyl-(4-vinyl Prepared using a variety of bifunctional protein coupling agents such as sulfonates and benzoates. The present disclosure relates to a peptide-drug conjugate that can be prepared by any method disclosed in the art. It is further contemplated that the composition may be prepared using a suitable method such as those described in Hermanson (Ed.), 2008, (See Bioconjugate Techniques, 2nd edition).

[0114] 5.3 Pharmaceutical Compositions In one aspect, the present disclosure further provides a pharmaceutical composition comprising at least one peptide of the present disclosure. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of the compounds provided herein. It comprises a peptide and a pharma- ceutically acceptable excipient.

[0115] The pharmaceutical composition comprising the peptide can be administered to any physiologically acceptable carrier with a desired degree of purity. By mixing with a physiologically acceptable excipient, it can be prepared in the form of an aqueous solution or by lyophilization or other methods. (Remington's Pharmacy, 1980, Remington's Pharmaceutical Sciences) (See Washington's Pharmaceutical Sciences, 18th ed.).

[0116] The peptides of the present disclosure can be packaged, for example, in microcapsules or macroemulsions (Remington's References, supra; Park et al., 2005, Molecules 10:146-61; Malik et al., 2007, Curr. Dr. ug. Deliv. 4:141-51), as a sustained release formulation (Putney and Burke, 1998, Nature 1998, 11:131-132, 1998). Biotechnol. 16:153-57) or as liposomes (Maclean et al., 1997, Int. J. Oncol. 11:325-32; see Kontermann, 2006, Curr. Opin. Mol. Ther. 8:39-45) In particular, the composition may be formulated in any form suitable for delivery to the target cells / tissues.

[0117] The peptides provided herein can be prepared, for example, by coacervation techniques or interfacial polymerization. Microcapsules prepared by, for example, colloidal drug delivery systems (e.g. For example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules. Hydroxymethylcellulose or gelatin microcapsules in macroemulsions Encapsulation in cells and poly(methylmethacylate) microcapsules Such techniques are disclosed, for example, in the Remington publication mentioned above.

[0118] Encapsulation in liposomes, microparticles, microcapsules, compositions capable of expressing peptides In recombinant cells, receptor-mediated endocytosis (Wu and Wu, 1987, J. Biol. Chem. 26 2:4429-32), including construction of the nucleic acid as part of a retroviral or other vector. A variety of compositions and delivery systems are known, including, but not limited to, those described herein. In another embodiment, the composition can be used with a controlled release or It may be provided as a sustained release system. In one embodiment, the sustained release or controlled release A pump may be used to achieve this (Langer, supra; Sefton, 1987, Cr Ref. Biomed. Eng. 14:201-40; Buchwald et al., 1980, Surgery 88:507-16; and S (See Audek et al., 1989, N. Engl. J. Med. 321:569-74). In another embodiment, the polymer The materials can be used to administer prophylactic or therapeutic agents (e.g., peptides described herein) or to administer the Controlled or sustained release of the compositions provided herein can be achieved (Langer and Wissens, e (ed.) Literature, 1974, Medical Applications of Controlled Release ); Smolen and Ball (eds.), 1984, Controlled Drug Bioavailability, Pharmaceuticals Controlled Drug Bioavailability, Drug Product Design and Performance e); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61-1 26; Levy et al., 1985, Science 228:190-92; During et al., 1989, Ann. Neurol. 2 5:351-56; Howard et al., 1989, J. Neurosurg. 71:105-12; U.S. Patent No. 5,679,377; Nos. 5,916,597; 5,912,015; 5,989,463; and 5,128,326; PCT Publication WO 99 / (See WO 99 / 20253 and WO 15154.) Examples of polymers used in sustained release formulations include poly(2-hydroxybutyric acid), poly(2-hydroxybutyric acid), and poly(2-methylbutyric acid). Poly(ethyloxyethyl methacrylate), Poly(methyl methacrylate), Poly(acrylic acid), Poly( Ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolide (PLG), polyanhydrides, poly Poly(N-vinylpyrrolidone), Poly(vinyl alcohol), Polyacrylamide, Poly(ethylene Poly(lactide-co-glycolide) (PLGA), polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and poly(propylene glycol) (PPGA). In one embodiment, the sustained release formulation includes, but is not limited to, ethyl esters. The polymers used are inert, free of leachable impurities, storage stable, and sterile. and is biodegradable.

[0119] In yet another embodiment, the controlled release or sustained release system is directed to a specific target tissue, e.g. It can be placed near the nasal passages or lungs, thus requiring only a fraction of the systemic dose. (Goodson, 1984, Medical Applications of Controlled Release) Lease) vol. 2, 115-38. Controlled release systems are described, for example, in Langer, 1990, Science 249 The methods described herein may be performed using any technique known to those of skill in the art. Sustained release formulations can be produced that contain one or more peptides that have been described in US Pat. No. 4,525,633. 6,938, PCT Publications WO 91 / 05548 and WO 96 / 20698, Ning et al., 1996, Radiotherapy & O ncology 39:179-89; Song et al., 1995, PDA J. of Pharma. Sci. & Tech. 50:372-97; Cleek et al., 1997, Proc. Int'l. Symp. Control. Rel. Bioact. Mater. 24:853-54; and Lam et al., 1997, Proc. Int'l. Symp. Control Rel. Bioact. Mater. 24:759-6 0).

[0120] 5.4 Methods for Producing Peptides In yet another aspect, methods of making the various peptides provided herein are provided herein. The peptides provided herein can be synthesized by a variety of chemical synthesis methods, recombinant methods, or It can be produced by a combination of these.

[0121] The peptides provided herein can be produced by known conventional chemical synthesis. Methods for constructing the peptides of the present disclosure by means are known to those of skill in the art. The peptides obtained have primary, secondary, or tertiary structure and / or conformational characteristics similar to those of the native peptide. and may possess common biological properties, including peptide activity.

[0122] In some embodiments, the peptides provided herein can be administered using conventional stepwise solution or They can be prepared using solid phase synthesis (Merrifield, R.B., 1963, J. Am. Chem. Soc. 85: 2149-2154; Williams et al. (eds.), 1997, Chemical Approaches to the Synthesis of Peptides and Proteins. Roach (Chemical Approaches to the Synthesis of Peptides and Proteins) and its References cited in Atherton & Sheppard (eds.), 1989, Solid Phase Peptide Synthesis: Practical Applications Solid Phase Peptide Synthesis: A Practical Approach and its Applications (See cited references).

[0123] Alternatively, the peptides provided herein can be prepared by any method known in the art, e.g., as described in Liu et al., 1996, Tetrahedron. on Lett. 37(7):933-936; Baca et al., 1995, J. Am. Chem. Soc. 117:1881-1887; Tam et al., 1995, Int. J. Peptide Protein Res. 45:209-216; Schnolzer and Kent, Liu and Tam, 1994, J. Am. Chem. Soc. 116(10):4 Liu and Tam, 1994, Proc. Natl. Acad. Sci. USA 91:6584-6588; Yamas (Hiro and Li, 1988, Int. J. Peptide Protein Res. 31:322-334). This is particularly the case for Gly (G)-containing peptides. Another method useful for the synthesis of the peptides and peptide analogs of the invention is described by Nakagawa et al. This is described in the literature, 1985, J. Am. Chem. Soc. 107:7087-7092.

[0124] The peptides provided herein may be synthesized with one or more (D) amino acids. The choice of including (L) or (D)-amino acids depends, in part, on the desired properties of the peptide. - replacing all or part of the sequence of amino acids with the respective sequence of enantiomeric (D)-amino acids; In other words, each part of the peptide chain has an optical isomer structure. Reversing all or part of the sequence results in a retro analogue of the peptide. Combining sequence inversion with substitutions (from 1 to D, or from D to L) allows for retroinspection of peptides. Enantiomeric peptides, their retro analogs, and their retro analogs The retroinverso analogs retain significant morphological relationships to the parent peptide, in particular the parent and its retroinverted analogs. It is known to those skilled in the art that a high degree of similarity is often obtained for inverso analogs. This relationship and similarity is due to the biochemical properties of the peptides, particularly the respective peptides and analogs. This can be reflected in the high degree of binding of the peptide to its receptor protein. The synthesis of the above-mentioned compounds is described, for example, in Methods of Organic Chemistry (Houben-Wey l) Synthesis of Peptides and Peptidomimetics - Workbench (ed.) Vol. E22c (Editor-in-chief Goodman M.) 2004 (George Thieme Verlag Stutt gart, New York, and the references cited therein, all of which are incorporated herein by reference in their entirety. No. 6,399,433, which is incorporated herein by reference in its entirety.

[0125] Amino acid modifications include altering natural amino acids to produce unnatural amino acids. Derivatives of the peptides of the invention using unnatural amino acids are incorporated herein by reference in their entirety. Incorporated by Christopher J. Noren, Spencer J. Anthony-Cahill, Michael C. Gr iffith, as described in Peter G. Schultz's 1989 Science, 244:182-188 paper, Site-specific incorporation of unnatural amino acids into peptides by chemical synthesis or during biosynthesis. It can be produced by:

[0126] Peptide mimetics that are structurally similar to therapeutically useful peptides have the same therapeutic effect or In general, peptidomimetics can be used to produce a prophylactic effect. Structurally similar to peptides (i.e., polypeptides with biochemical properties or pharmacological activity) However, methods known in the art and the following references are also included: Spatola, 1983, Pe Peptide Backbone Modifications; Morely, 1098, Trends Pha Rma Sci, pp. 463-468; Hudson et al., 1979, Int J Pept Prot Re 14: 177-185 (--CH 2-NH--, --CH2-CH2--); Spatola et al., 1986, Life Sci 38:1243-1249 (--CH2-S--); H ann, 1982, J. Chem. Soc. Perkin. Trans. I 307-314 (--CH=CH--, cis and tran Almquist et al., 1980, J. Med. Chem. 23: 1392 (--COCH2--); Jennings-Whit e et al., 1982, Tetrahedron Lett 23:2533 (--COCH2--); Szelke et al., 1982, Eur opean Appln. EP 45665 CA: 97: 39405 (--CH(OH)CH2--); Holladay et al., 1983, Tet rahedron Lett 24:4401-4404 (--C(OH)CH2--); and Hruby, 1982, Life Sci 31:189 -199 (--CH2-S--); each of which is incorporated herein by reference. By the method of the above, --CH2-NH--, --CH2S--, --CH2-CH2--, --CH=CH-(cis and trans), --COCH2--, --CH(OH)CH2--, and --CH2SO--; Thus, having one or more peptide bonds replaced.

[0127] In another embodiment, a particularly preferred non-peptide bond is --CHNH--. Peptide mimetics have the potential to be, for example, more economical to produce, more chemically stable, and have enhanced pharmacological properties. altered biological properties (half-life, absorption, potency, efficacy, etc.), specificity (e.g., broad-spectrum biosynthesis, These may have significant advantages over peptide embodiments, including reduced immunogenicity, reduced cytotoxicity, and reduced antigenicity. do.

[0128] Various designs of peptidomimetics are possible. For example, Conformation stabilized cyclic peptides are specifically contemplated, and are incorporated herein by reference in their entirety. Nos. 5,192,746, 5,576,423, 5,051,448, and No. 5,559,103 describes several methods for making such peptides. The synthesis of non-peptidic peptides that mimic peptide sequences is also known in the art. Eldred et al., 1994, J. Med. Chem., incorporated herein by reference in its entirety. 37:3882) describe non-peptide antagonists that mimic peptide sequences. The synthesis of a series of such peptides is further elucidated (the entire contents of which are incorporated herein by reference). (See Ku et al., 1995, J. Med. Chem 38:9, incorporated herein by reference).

[0129] Further modifications may be performed after synthesis. For example, the peptides are incorporated herein by reference in their entirety. The compound was published on April 17, 2003 under the title 20030072737-A1, the disclosure of which is incorporated herein by reference. No. 10 / 188,905, filed July 1, 2003, which discloses chemically modified EPO. No. 10 / 612,665, filed Dec. 29, 2000, and U.S. patent application Ser. No. 09 / 753,132, filed Dec. 29, 2000. Therefore, they can be further chemically modified, i.e., carbamylated, acetylated, succinylated, etc. The amino acids can be converted into aryl, guanidinium, nitrated, trinitrophenylated, amidine, etc.

[0130] Furthermore, the peptide may consist of a mutein of the recombinant peptide. , substitutions, deletions including internal deletions, additions including additions resulting in fusion proteins, or amino acid sequences. Conservative substitutions of amino acid residues within and / or adjacent to the amino acid sequence may be included, but may not be used to Recombinant tissue-protective cytokines for the protection, restoration, and enhancement of human cells, tissues, and organs No. 6,399,434, entitled "Compounds and Nucleic Acids Encoding the Same," which is incorporated herein by reference in its entirety. As previously disclosed in the incorporated herein by reference, "silent" changes and non-conservative alterations may be used. Amino acid changes and larger insertions and deletions can occur.

[0131] Either conservative or non-conservative amino acid substitutions may be made at one or more amino acid residues. Both conservative and non-conservative substitutions can be made. Conservative substitutions are those that have similar side chains. They occur within a family of related amino acids within the Acids are divided into four families: (1) acidic = Asp (D), Glu (G); (2) basic = Lys (K), Arg (R). , His (H); (3) Nonpolar (hydrophobic) = Cys (C), Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Met (M), Trp (W), Gly (G), Tyr (Y); and (4) polar uncharged = Asn (N), They can be divided into Gln (Q), Ser (S), and Thr (T). Non-polar, strongly hydrophobic = Ala (A), V Al (V), Leu (L), Ile (I), Met (M), Phe (F); and moderately hydrophobic = Gly (G), Pro (P) Alternatively, the amino acid sequence can be subdivided into the amino acids Cys (C), Tyr (Y), and Trp (W). The trio are: (1) acidic = Asp (D), Glu (G); (2) basic = Lys (K), Arg (R), His (H), ( 3) Aliphatic = Gly (G), Ala (A), Val (V), Leu (L), Ile (I), Ser (S), Thr (T), where , Ser (S) and Thr (T) are grouped separately as aliphatic hydroxyls as required. (4) aromatic = Phe (F), Tyr (Y), Trp (W); (5) amide = Asn (N), Glu (Q); and (6) Sulfur-containing = Cys (C) and Met (M) (the entirety of which is incorporated herein by reference) Stryer and Freeman (eds.), 1995, Biochemistry, (see 4th edition).

[0132] Alternatively, mutations can be introduced into all or part of the coding sequence for the peptide, such as by saturation mutagenesis. The resulting mutations can be introduced randomly along the genomic DNA and identified as mutants that retain activity. After mutagenesis, the encoded The peptides can be recombinantly expressed and the activity of the recombinant peptides can be determined. do.

[0133] In another embodiment, the peptide extends the half-life of a peptide or enhances the activity of a combination of peptides. In an effort to improve tissue protection, polymers (such as polyethylene glycol), sugars, or additives have been used. It may be further modified through the addition of additional proteins (such as fusion constructs). Examples are given in WO / 04022577 A3 and WO / 05025606 A1, which are incorporated herein by reference. It has been disclosed.

[0134] The conjugation chemistry chosen and the reaction already present or created on the peptide Depending on the number of reaction sites, one, two, or a selected number of polymers can be added in a reproducible manner. The primary mode of attachment of PEG and its derivatives to peptides is via the peptide amino acid sequence. Non-specific binding via acid residues (U.S. Pat. Nos. 4,088,538, 4,496,689, 4,4 (See, e.g., US Pat. Nos. 14,147, 4,055,635, and PCT WO 87 / 00056.) Another method for attaching PEG to peptides is to The mode of action is via non-specific oxidation of glycosyl residues on glycopeptides (WO 94 / 053 32) In these nonspecific methods, PEG is randomly coupled to reactive residues on the peptide backbone. It is added in a non-specific manner at the dam.

[0135] In certain embodiments, the peptides provided herein are prepared by recombinantly producing a parent peptide, which is then These can be produced by chemically modifying the parent peptide without using any of the methods described herein. Certain peptides provided herein are recombinantly produced P8 peptides as described in the Examples section below. It can be produced by chemical modification.

[0136] Producing peptides by recombinant methods is known in the art. More specifically, Polynucleotides can be isolated by a number of techniques, including isolating genomic or cDNA molecules from a suitable source. The method can be used to identify the target gene. or for use as a query sequence for database searches. The nucleotide sequence corresponding to the amino acid sequence described above can be "back-translated" from the amino acid sequence. or regions of amino acid identity with peptides whose coding DNA sequences have been identified This can be achieved by identification of the well-known polymerase chain reaction (PCR) procedure. The procedure can be used to isolate and amplify DNA sequences encoding human presenilin-1. The oligonucleotides that define the desired termini of the DNA fragment combination are 5' and 3' primers. The oligonucleotide is used as a primer to identify the recognition site of a restriction endonuclease. and facilitating insertion of the amplified combination of DNA fragments into an expression vector. PCR technology is described in Saiki et al., 1988, Science 239:487; Wu et al. (eds.), 1989, Recombinant DNA Methodology, pp. 189-196; and Innis et al. (eds.), 1 990, PCR Protocols: A Guide to Methods and Applications ications).

[0137] Polynucleotide molecules of the present disclosure (e.g., P8 polynucleotides) include single-stranded and double-stranded polynucleotides. Both stranded forms of DNA and RNA are included, as well as the corresponding complementary sequences. DNA includes, e.g. , cDNA, genomic DNA, chemically synthesized DNA, DNA amplified by PCR, and combinations thereof. The polynucleotide molecules of the present disclosure include full-length genes or cDNA molecules, as well as fragments thereof. The polynucleotides of the present disclosure may be derived from a human source, but may also be derived from any combination of The present disclosure includes those derived from non-human species as well.

[0138] An "isolated polynucleotide" refers to a polynucleotide that has been isolated from a natural source. , the polynucleotide is separated from adjacent gene sequences present in the genome of the organism from which it was isolated. A polynucleotide, such as a PCR product, a cDNA molecule, or an oligonucleotide. In the case of polynucleotides that are enzymatically or chemically synthesized from a template, A polynucleotide resulting from such a process is understood to be an isolated polynucleotide. An isolated polynucleotide is one that is present in the form of a separate fragment or is associated with a larger polynucleotide. In one embodiment, the present disclosure relates to a polynucleotide that is a component of a construct. The present invention relates to an isolated polynucleotide that is substantially free of endogenous material. The nucleotides may be isolated in substantially pure form and their component nucleotides by standard biochemical methods. DNA that has been isolated at least once in an amount or concentration that allows for sequence identification, manipulation, and recovery, or Preferably, the nucleic acid is derived from RNA (Sambrook et al., 1989, Molecular Cloning, Laboratory Press, 1999). (See Molecular Cloning. A Laboratory Manual, 2nd ed.). Such sequences are , an open sequence that is not interrupted by internal non-translated sequences that are typically present in eukaryotic genes Provided and / or constructed in the form of a reading frame or in trans. The sequences can be 5' or 3' from the open reading frame and are This does not interfere with the manipulation or expression of the domain.

[0139] The expression, isolation, and purification of the parent peptide can be carried out by any method, including, but not limited to, the following: The isolated nucleic acids of the present disclosure can be expressed in pDC409 vector (Giri et al., supra). 1990, EMBO J. 13: 2821) or the derived pDC412 vector (Wiley et al., 1995, Immunity 3:673). pDC400 series vectors The vectors are useful in transient mammalian expression systems such as CV-1 or 293 cells. The isolated nucleic acid can be ligated into an expression vector, such as the pDC312, pDC316, or pDC317 vector. All pDC300 series vectors contain the SV40 replication origin, CMV promoter, and adenovirus The gene includes the triplicate leader of SV40, and the polyA and termination signals of SV40, and is capable of expressing the gene in CHO cells or their derivatives. Stable mammalian expression systems such as the pMT2 or pED expression vectors (Kaufman et al., Ref., 1991, Nucleic Acids Res 19: 4485-4490; and Pouwels et al., 1985, Clones Cloning Vectors. A Laboratory Manual and GATEW Other expression control sequences and clones, such as the AY vector (Life Technologies; Rockville, Md.), Glycosylating techniques can also be used to recombinantly produce peptides. The isolated nucleic acid of the present disclosure is integratively inserted into a GATEWAY vector, such as pDONR201, that contains an attP sequence. Entry vector into the GATEWAY system containing the isolated nucleic acid of the present disclosure This entry vector can be provided as the pDC400 and pDC300 series. The vector can further be recombined with other appropriately tailored expression control sequences, such as those of Suitable expression control sequences for the expression of recombinant peptides are known in the art. The method is also described in Kaufman, 1990, Methods in Enzymology 185, 537-566. As used herein, "operably linked" means that the appropriate molecule (such as a polymerase) is When present, the peptide encoded by the polynucleotide is expressed. The disclosed polynucleotides and expression control sequences are located in a construct, vector, or cell. In one embodiment of the present disclosure, the at least one expression control sequence is a recombinant operably linked to a polynucleotide of the present disclosure in the host cell or its progeny, The nucleotides and / or expression control sequences can be, for example, transformed or transfected. In another embodiment of the present disclosure, the vector is introduced into the host cell by recombinant DNA technology, such as recombinant vectors, recombinant vectors, or any other suitable method. In an embodiment, at least one expression control sequence is provided that encodes a polypeptide encoding a peptide of the present disclosure. The nucleic acid sequence is integrated into the genome of the recombinant host cell so that it is operably linked to the nucleotide sequence. In further embodiments of the present disclosure, the at least one expression control sequence is a transcription factor. The present disclosure provides a method for the production of a polypeptide comprising the steps of: is operably linked to a nucleotide.

[0140] In addition, a sequence (native or heterologous) encoding an appropriate signal peptide is incorporated into the expression vector. The choice of signal peptide or leader depends on the sequence in which the recombinant peptide is produced. The degree of expression of the vector may depend on factors such as the type of host cell being used. Examples of heterologous signal peptides that function in a nucleic acid sequence include the interferon-dependent signal peptides described in U.S. Pat. No. 4,965,195. The signal sequence of leukin-7 (IL-7); as described in Cosman et al., 1984, Nature 312:768 the signal sequence of the interleukin-2 receptor described in EP 367,566; -4 receptor signal peptide; the type I interleukin-1 receptor signal peptide described in U.S. Pat. No. 4,968,607; and the type II interleukin-1 receptor signal peptide described in EP 460,846. The DNA sequence of the signal peptide (secretory leader) determines when the DNA is first transcribed. The polynucleotides of the present disclosure are then used to express the mRNA, which is translated into a fusion peptide containing a signal peptide. The signal transduction can be fused in frame to a nucleotide that is functional in the intended host cell. The null peptide promotes extracellular secretion of the peptide. The signal peptide directs the peptide out of the cell. The signal peptide is cleaved off the peptide when the peptide is secreted. The position(s) predicted by the computer program differ from those predicted by the recombination gene. The expression of the peptide can vary depending on factors such as the type of host cell employed. It will also be appreciated that peptide preparations may be prepared by cleavage of the signal peptide at two or more sites. The peptide may comprise a mixture of peptide molecules having different N-terminal amino acids arising from

[0141] Established methods for introducing DNA into mammalian cells have been described (Kaufman, 1990, Large Scale Mammalian Cell Culture, pp. 15-69). Lipofe Lipofectamine lipid reagent (Gibco / BRL) Additional preparations using commercially available reagents such as Lipofectamine-Plus lipid reagent Cells can be transfected using the same protocol (Felgner et al., 1987, Proc. Natl. Acad. Sci. USA 84: 7413-7417). In addition, electroporation Using the method described in Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual. in mammalian cells using conventional procedures such as those in the 2nd Edition of the Protease Activity Report (Protease Activity Report: A Laboratory Manual). The selection of stable transformants can be performed using, for example, cytotoxic drugs. This can be done using methods known in the art, such as resistance to stimulants. In the literature, 1990, Meth. in Enzymology 185:487-511, Several selection schemes are described. Strains suitable for DHFR selection are DHFR-deficient. The most likely candidate is the CHO strain DX-B11, which is a strain that has been shown to be highly resistant to HIV infection (Urlaub and Chasin, Proc. Natl. Acad. Sci. USA 77:4216-4220, 1980). A plasmid expressing DHFR cDNA could be introduced into strain DX-B11. Only cells containing the plasmid can grow in the appropriate selection medium. Other examples of selectable markers that can be incorporated into the vector include G418 and hygromycin B. Examples of such vectors include cDNAs that confer resistance to antibiotics. Selection can be based on resistance to these compounds.

[0142] Alternatively, the gene product can be obtained by homologous recombination, or "gene targeting" techniques. Such techniques can be used to insert exogenous transcriptional regulatory elements into specific, predefined sites on the genome. The endogenous polynucleotide sequence of interest can be expressed by introducing a promoter such as a CMV promoter. The location of integration into the host chromosome or genome is determined based on the known location of the gene and This can be readily determined by one of skill in the art given the sequence. In one embodiment, the present disclosure again provides: To produce increased amounts of gene product without the need to isolate the gene itself from the host cell The introduction of exogenous transcriptional control elements in combination with an amplifiable gene is also contemplated. The practice of recombination or gene targeting is described in Schimke et al., 1987, Methods in Enzyme Synthesis, 1990, 1992, 1995, 1996, 1997, 1998, 19 ...0, 1 logy 151:85-104, and Capecchi et al., 1989, TIG 5:70-76.

[0143] Several types of cells can act as suitable host cells for the expression of peptides. The main cells include, for example, the monkey kidney cell line COS-7 (ATCC CRL 1651; Gluzman et al., 1981, C ell 23:175), L cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster Ovarian (CHO) cells, HeLa cells, BHK (ATCC CRL 10) cell line, McMahan et al., 1991, EMBO J. The antibody was derived from the African green monkey kidney cell line CV1 (ATCC CCL 70) described by CV1 / EBNA cell lines, human kidney 293 cells, human epidermal A431 cells, human Colo205 cells, and other transformed Transgenic primate cell lines, normal diploid cells, cell lines derived from in vitro culture of primary tissues , primary explants, HL-60, U937, HaK or Jurkat cells. Alternatively, lower organisms such as yeast It may be possible to produce the peptide in eukaryotes or prokaryotes such as bacteria. Suitable yeast strains for this purpose include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces cerevisiae, strains of Heterologous Peptides, including Heterologous Mycobacterium sp., Candida albicans, or any yeast strain capable of expressing a heterologous peptide. Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or Any bacterial strain capable of expressing a heterologous peptide is included. When produced in vivo, appropriate sites may be phosphorylated or glycerol may be added to obtain a functional peptide. It may be necessary to modify the peptides produced therein by glycosylation. Such covalent attachment can be accomplished using known chemical or enzymatic methods. The isolated polynucleotides of the present disclosure can also be incorporated into suitable control sequences in one or more insect expression vectors. They can be operably linked and produced by using an insect expression system. Materials and methods for the plasmid / insect cell expression system are described, for example, in the literature, by Invitrogen, San Diego, Calif., US Such methods are commercially available in kit form from AB (the MaxBac.RTM. kit), and are described in detail in the literature. Summers and Smith, Texas Agricultural Exp. Laboratory Station Bulletin No. 1555 (1987), and Luckow and Summers, Bio / Tech As used herein, the term "antibody" refers to a compound that is known in the art, as described in J. Med. Chem. 6:47 (1988). When the insect cell is transformed, it is capable of expressing a polynucleotide of the present disclosure. Cell-free translation systems can also be used to generate RNAs derived from the polynucleotide constructs disclosed herein. Typically, at least one expression control sequence is used to produce a peptide. A host cell containing an isolated polynucleotide of the present disclosure operably linked to a sequence is referred to as a "recombinant host cell." The "chief cell".

[0144] The peptide is produced by culturing transformed host cells under culture conditions suitable for expressing the recombinant peptide. The resulting expressed peptides can then be purified by gel filtration and ion exchange. From such cultures, known purification processes such as ion exchange chromatography can be used to obtain For example, the peptide may be purified from the culture medium or cell extracts. Affinity columns containing drugs that bind to the antibody; Concanavalin A agarose, Heparin, Toyopearl® ) or one or more column preparations on affinity resins such as Cibacrom blue 3GA Sepharose®. Process: Using phenyl ether, butyl ether, or propyl ether resins or one or more steps including hydrophobic interaction chromatography; or immunoaffinity chromatography. Alternatively, the peptides of the present disclosure may be expressed in a form that facilitates purification. For example, it is a maltose-binding peptide (MBP), glutathione-S-transferase The polypeptide may be expressed as a fusion peptide, such as that of guanidine triphosphate (GST) or thioredoxin (TRX). Kits for expression and purification of fusion peptides such as those listed above were purchased from New England BioLab (Be These are commercially available from Peverly, Mass., Pharmacia (Piscataway, NJ) and InVitrogen. The peptides can also be tagged with epitopes and then subjected to specific It can be purified by using antibodies. One such epitope (Flag) is , available from Kodak (New Haven, Conn.). Finally, hydrophobic RP-HPLC media, e.g. , one or more reversed-phase high-performance liquid crystals using silica gel with pendant methyl or other aliphatic groups A chromatographic (RP-HPLC) step can be used to further purify the peptide. Some or all of the above purification steps may be performed in various combinations to produce a substantially homogeneous isolated recombinant peptide. Such purified peptides can also be used to provide peptides to other mammalian It is substantially free of animal peptides and is defined in accordance with the present disclosure as a "purified peptide." Such purified peptides of the disclosure include purified antibodies that bind to the presenilin peptides of the disclosure. The peptides of the present disclosure include sequences encoding the peptides, fragments, variants, binding partners, etc. A transgenic cell is characterized by a somatic or germ cell that contains a polynucleotide that As a product of a transgenic animal, for example, milk production from transgenic cows, goats, pigs, or sheep. It may be expressed as a fraction.

[0145] Peptide binding of the present disclosure, such as monoclonal antibodies raised against the peptides of the present disclosure. The expressed peptides can also be affinity purified using peptide-containing affinity columns. These peptides can be purified, for example, by affinity chromatography using conventional techniques in a high salt elution buffer. The protein is removed from the ram and then dialyzed or utilized in a lower salt buffer for use. Depending on the affinity matrix, it can be removed by changing the pH or other components, or The affinity moiety can be competitively removed using a natural substrate for the affinity moiety, such as a peptide derived from In this aspect of the disclosure, a peptide of this disclosure or another peptide capable of interacting with the peptide of the disclosure is provided. Peptide-binding peptides, such as anti-peptide antibodies of the peptides of the present disclosure, can be used to bind to the peptides of the present disclosure on their surfaces. A column chromatograph suitable for identifying, isolating, or purifying cells expressing a peptide. It can be attached to a solid support, such as a fee matrix or similar substance.

[0146] Attachment of peptide-binding peptides to a solid-phase contact surface can be accomplished by any number of techniques. For example, magnetic microspheres can be coated with these peptide-binding peptides to form magnetic The suspension of the cell mixture can be held in the incubation vessel by the magnetic field. The peptide-binding peptide of the present disclosure is then contacted with a solid phase having such a peptide-binding peptide on its surface. Cells bearing the peptide bind to the immobilized peptide-binding peptide, and unbound cells are then This affinity binding method allows for the purification and screening of such peptide-expressing cells from solution. Methods for releasing positively selected cells from a solid phase are useful for isolating or isolating the cells. These methods are well known in the art and include, for example, the use of enzymes. Such enzymes are preferably , which are non-toxic and non-harmful to cells and are directed to cleave cell surface binding partners Alternatively, a mixture of cells suspected of containing peptide-expressing cells of the present disclosure may be First, one can incubate with a biotinylated peptide-binding peptide of the present disclosure. The incubation period is typically long enough to ensure sufficient binding to the peptides of the present disclosure. The resulting mixture is then incubated with avidin The beads are passed through a column packed with avidin, which induces the binding of the avidin to the biotin. The high affinity of the avidin provides binding of peptide-bound cells to the beads. The use of beads is known in the art (Berenson et al., 1986, J. Cell. Biochem. , 1OD:239). Washing of unbound material and release of bound cells is carried out using conventional methods. .

[0147] The desired purity depends on the intended use of the peptide. For example, if the peptide is to be administered in vivo, In such cases, a relatively high degree of purity is desired. During analysis by gel electrophoresis (SDS-PAGE), peptide bands corresponding to other peptides were detectable. The peptides are purified so that they are not amenable to differential glycolysis. Cosylation, differential post-translational processing, etc., can be visualized by SDS-PAGE. As will be appreciated by those skilled in the relevant art. In some embodiments, the peptides of the present disclosure are to virtual homogeneity as indicated by a single peptide band upon analysis by GE. The peptide bands were identified by silver staining, Coomassie blue staining, or autoradiography. The peptide can be visualized by radiolabeling (if the peptide is radiolabeled).

[0148] 5.5 Uses of Peptides and Pharmaceutical Compositions In one embodiment, the present invention relates to a method for the synthesis of presenilin-1 (PS-1) and / or presenilin-2 (PS-2) and beta- A method for attenuating binding of amyloid precursor protein (β-APP) comprising administering to a subject a subject in need thereof a therapeutically effective amount of β-APP, comprising administering to the subject a therapeutically effective amount of β-APP, Provided herein are methods that include contacting a cell with a peptide that inhibits the activation of some In embodiments, the peptides provided herein inhibit the expression of beta amyloid precursor proteins in cells. Reduces the binding of protein (β-APP) to presenilin-1 (PS-1) and / or presenilin-2 (PS-2) In some embodiments, the optical fibers are attenuated (e.g., partially attenuated) by about 10%. The peptides provided herein are capable of activating presenilin-1 (PS-1) and / or presenilin-2 (PS -2) and beta-amyloid precursor protein (β-APP) binding by at least about 20%. In some embodiments, the peptides provided herein inhibit presenilin-1 in cells. (PS-1) and / or presenilin-2 (PS-2) and beta-amyloid precursor protein (β-APP) In some embodiments, the peptides provided herein attenuate binding by at least about 30%. The peptides bind to presenilin-1 (PS-1) and / or presenilin-2 (PS-2) and beta-amino acids in cells. The binding of β-APP precursor protein (β-APP) is attenuated by at least about 40%. In one embodiment, the peptides provided herein are capable of activating presenilin-1 (PS-1) and / or The binding of presenilin-2 (PS-2) and beta-amyloid precursor protein (β-APP) was at least In some embodiments, the peptides provided herein reduce intracellular Presenilin-1 (PS-1) and / or presenilin-2 (PS-2) and beta-amyloid precursor protein In some embodiments, the binding of the protein (β-APP) is attenuated by at least about 60%. The peptides provided to the subject react with presenilin-1 (PS-1) and / or presenilin-2 (PS-2) in cells. ) to beta-amyloid precursor protein (β-APP) by at least about 70%. In some embodiments, the peptides provided herein inhibit the expression of presenilin-1 (P S-1) and / or presenilin-2 (PS-2) and beta-amyloid precursor protein (β-APP) In some embodiments, the peptides provided herein attenuate the expression of In cells, tide binds presenilin-1 (PS-1) and / or presenilin-2 (PS-2) and beta-amyloides. In some embodiments, the binding of β-APP is attenuated by at least about 90%. In some embodiments, the peptides provided herein are capable of activating presenilin-1 (PS-1) and / or presenilin-2 (PS-3) in cells. The binding of PS-2 to beta-amyloid precursor protein (β-APP) was suppressed by at least approximately Attenuates by 95%.

[0149] In one aspect, a method of attenuating the production of amyloid beta (Aβ) in a cell comprises the steps of: Provided herein are methods comprising contacting said cells with a peptide provided in. In some embodiments, the peptides provided herein reduce the production of Aβ in cells. In some embodiments, the peptides provided herein reduce the expression of Attenuates intracellular Aβ production by at least about 20%. The peptides provided in the present invention attenuate the production of Aβ in cells by at least about 30%. In some embodiments, the peptides provided herein inhibit the production of Aβ in cells by at least about 4 In some embodiments, the peptides provided herein attenuate intracellular A In some embodiments, the method provides a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a therapeutically effective amount of a medicament for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a medicament for the treatment of atopic dermatitis, and The peptide reduces the production of Aβ in cells by at least about 60%. In this regard, the peptides provided herein attenuate the production of Aβ in cells by at least about 70%. In some embodiments, the peptides provided herein inhibit the production of Aβ in cells. In some embodiments, the peptides provided herein attenuate the expression level of The method comprises the steps of: attenuating the production of Aβ in a cell by at least about 90%. The peptides provided herein attenuate the production of Aβ in cells by at least about 95%. In an exemplary embodiment, the cell is a retinal cell.

[0150] In another aspect, a method of attenuating production of amyloid beta (Aβ) in a subject comprises the steps of: administering to the subject an effective amount of a peptide as provided herein or a pharmaceutical composition comprising the same. In some embodiments, methods are provided herein that include the use of peptides provided herein. In some embodiments, the tide attenuates the production of Aβ in the plasma of the subject by at least about 10%. In the present invention, the peptides provided herein are capable of suppressing the production of Aβ in the plasma of a subject by at least about 20%. In some embodiments, the peptides provided herein attenuate the plasma concentration of In some embodiments, the method provides a method for the treatment of Aβ by at least about 30%. The peptides described herein attenuate the production of Aβ in the plasma of a subject by at least about 40%. In some embodiments, the peptides provided herein are useful for reducing the production of Aβ in the plasma of a subject. In some embodiments, the peptides provided herein reduce the expression of both In some embodiments, the present invention attenuates the production of Aβ in the plasma of the elephant by at least about 60%. The peptides provided herein attenuate the production of Aβ in the plasma of a subject by at least about 70%. In some embodiments, the peptides provided herein are useful for reducing Aβ production in the plasma of a subject. In some embodiments, the peptides provided herein attenuate the proliferation of the peptides by at least about 80%. In some embodiments, the tide attenuates the production of Aβ in the plasma of the subject by at least about 90%. In the present invention, the peptides provided herein are capable of suppressing the production of Aβ in the plasma of a subject by at least about 95%. To attenuate.

[0151] In some embodiments, the peptides provided herein are useful for inhibiting the production of Aβ in the CSF of a subject. In some embodiments, the peptides provided herein attenuate the expression level by at least about 10%. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of Aβ to the subject. In this regard, the peptides provided herein are capable of suppressing the production of Aβ in the CSF of a subject by at least about 30%. In some embodiments, the peptides provided herein reduce CSF activity in a subject by %. In some embodiments, the method of the present invention provides a method for the treatment of Aβ by attenuating Aβ production in a subject by at least about 40%. The peptides provided herein attenuate the production of Aβ in the CSF of a subject by at least about 50%. In some embodiments, the peptides provided herein are useful for reducing Aβ production in the CSF of a subject. In some embodiments, the peptides provided herein attenuate the proliferation of the peptides by at least about 60%. The tide attenuates the production of Aβ in the CSF of the subject by at least about 70%. In some embodiments, the peptides provided herein inhibit the production of Aβ in the CSF of a subject by at least about In some embodiments, the peptides provided herein attenuate CS in a subject by 80%. In some embodiments, the present invention provides a method for the treatment of Aβ comprising administering to a subject a therapeutically effective amount of at least about 90% of Aβ production in a subject. The peptides provided herein attenuate the production of Aβ in the CSF of a subject by at least about 95%.

[0152] In yet another aspect, there is provided a method of attenuating amyloid beta activity in a cell, comprising the steps of: Provided herein are methods comprising contacting said cells with a peptide provided in. In yet another aspect, a method of attenuating amyloid beta activity in a subject comprises administering to said subject a therapeutically effective amount of a compound as provided herein. and administering to the subject an effective amount of the peptide or a pharmaceutical composition containing the same. Non-limiting examples of amyloid-β activity include amyloid-β-inducing or -mediating Thus, in certain embodiments, the peptides provided herein are , attenuating (e.g., partially attenuating) amyloid-β-induced signaling. Other non-limiting examples of dopamine-induced signaling include glucose transporters, NMDARs, AMP-activators, and the like. AR and acetylcholine receptors, activation of inflammatory signaling pathways, and activation of GSK-3, CDK5, P This includes activation of one or more kinases, including but not limited to KC, PKA, and Erk1 / 2. The activities include, but are not limited to, interaction (including blocking) with receptors. Channel blockage, disruption of calcium homeostasis, mitochondrial oxidative stress, energy metabolism These may include metabolic disorders, abnormal glucose regulation and / or neuronal cell death.

[0153] In some embodiments, the peptides provided herein inhibit amyloid beta activity in cells. Attenuate the activity (e.g., amyloid-β induced signaling) by at least about 10%. In embodiments, the peptides provided herein inhibit amyloid beta activity in cells (e.g., In some embodiments, the amyloid β-induced signaling is attenuated by at least about 20%. The peptides provided herein inhibit intracellular amyloid beta activity (e.g., amyloid In some embodiments, the method of the present invention attenuates β-induced signaling by at least about 30%. The peptides provided herein inhibit amyloid-β activity in cells (e.g., amyloid-β-induced sigma). In some embodiments, the method provides a method for reducing the amount of cytotoxicity (null transmission) of a cytotoxic agent provided herein by at least about 40%. The peptides that are produced inhibit Aβ activity (e.g., Aβ-induced signaling) in cells. Attenuates by at least about 50%. In some embodiments, the peptides provided herein inhibits Aβ activity (e.g., Aβ-induced signaling) in cells by at least about In some embodiments, the peptides provided herein attenuate the expression of the IL-1 protein in cells by 60%. Attenuate Aβ activity (e.g., Aβ-induced signaling) by at least about 70% In some embodiments, the peptides provided herein inhibit intracellular amyloid beta. Attenuates activity (e.g., amyloid-β-induced signaling) by at least about 80%. In embodiments, the peptides provided herein inhibit intracellular amyloid beta activity (e.g., , amyloid-β induced signaling) by at least about 90%. In this regard, the peptides provided herein are intended to suppress intracellular amyloid beta activity (e.g., amyloid In a specific embodiment, the cells are These are retinal cells.

[0154] In some embodiments, the peptides provided herein are used to treat amyloidosis in a subject. Attenuates amyloid beta activity (e.g., amyloid beta-induced signaling) by at least about 10%. In some embodiments, the peptides provided herein are used to reduce amyloid beta activity ( For example, it attenuates amyloid-β-induced signaling by at least about 20%. In embodiments, the peptides provided herein are used to reduce amyloid beta activity (e.g., , amyloid-β induced signaling) by at least about 30%. In this regard, the peptides provided herein are intended to reduce amyloid beta activity (e.g., amyloid β activity) in a subject. In some embodiments, the method attenuates IL-6 induced signaling by at least about 40%. The peptides provided herein are intended to reduce amyloid beta activity (e.g., amyloid In some embodiments, the method of the present invention attenuates β-induced signaling by at least about 50%. The peptides provided herein are intended to be used to inhibit amyloid beta activity (e.g., amyloid beta induction) in a subject. In some embodiments, the method of the present invention provides a method for reducing the amount of signal transduction that occurs during cell death by at least about 60%. The peptide provided may be used to inhibit amyloid beta activity (e.g., amyloid beta-induced signaling) in a subject. In some embodiments, the method provided herein attenuates the transmission of radiation (radiation) by at least about 70%. The peptide can be used to inhibit amyloid-beta activity (e.g., amyloid-beta induced signaling) in a subject. In some embodiments, the peptides provided herein attenuate the expression level of The method comprises the steps of: reducing amyloid-beta activity (e.g., amyloid-beta induced signaling) in a subject; In some embodiments, the peptides provided herein attenuate both the and reducing amyloid-β activity (e.g., amyloid-β-induced signaling) in the elephant by at least about 95%. % attenuation.

[0155] In one embodiment, the amyloid beta is amyloid beta 36, ​​amyloid beta 37, amyloid beta 38 , Amyloid beta 39, Amyloid beta 40, Amyloid beta 41, Amyloid beta 42, Amyloid beta 43 , Amyloid beta 44, Amyloid beta 45, Amyloid beta 46, Amyloid beta 47, Amyloid beta 48 , amyloid beta 49, amyloid beta 50, amyloid beta 51, or amyloid beta 52, or any of them In another embodiment, the amyloid beta is amyloid beta 40. In another embodiment, the amyloid beta is amyloid beta 42.

[0156] In yet another aspect, there is provided a method of attenuating the production of tau protein in a cell, comprising the steps of: Provided herein are methods for treating a cancer cell comprising contacting said cell with a peptide provided herein. In some embodiments, the peptides provided herein inhibit the production of tau in cells. Attenuates by at least about 10%. In some embodiments, the peptides provided herein In some embodiments, the present invention reduces the production of tau in cells by at least about 20%. The peptides provided herein attenuate the production of tau in cells by at least about 30%. In some embodiments, the peptides provided herein inhibit or at least inhibit the production of tau in cells. In some embodiments, the peptides provided herein also attenuate the expression of cellular In some embodiments, the method provides for the treatment of tau production in a subject by at least about 50%. The peptides provided attenuate intracellular tau production by at least about 60%. In embodiments, the peptides provided herein inhibit the production of tau in cells by at least about 70%. In some embodiments, the peptides provided herein attenuate tau expression in cells. In some embodiments, the production of the agonist provided herein is attenuated by at least about 80%. The peptide attenuates the production of tau in a cell by at least about 90%. The peptides provided herein attenuate the production of tau in cells by at least about 95%. In a specific embodiment, the cell is a retinal cell.

[0157] In yet another aspect, there is provided a method of attenuating production of tau protein in a subject, comprising: administering to the subject a peptide provided herein or a pharmaceutical composition comprising the same. In some embodiments, a method is provided herein. attenuates the amount of tau in the plasma of the subject by at least about 10%. The peptides provided herein attenuate the amount of tau in the plasma of a subject by at least about 20%. In some embodiments, the peptides provided herein are useful for reducing tau levels in the plasma of a subject. In some embodiments, the peptides provided herein reduce the amount of In some embodiments, the tide reduces the amount of tau in the plasma of the subject by at least about 40%. The peptides provided herein reduce the amount of tau in the plasma of a subject by at least about 50%. In some embodiments, the peptides provided herein are capable of increasing the levels of TA in the plasma of a subject. In some embodiments, the amount of nicotinamide or nicotinamide provided herein is reduced by at least about 60%. The peptide reduces the amount of tau in the plasma of the subject by at least about 70%. In some embodiments, the peptides provided herein reduce the amount of tau in the plasma of a subject by at least about 80%. In some embodiments, the peptides provided herein attenuate the plasma concentration of In some embodiments, the method provides a method for treating tau-related disorders comprising administering to a subject a therapeutically effective amount of tau to a subject, the method comprising administering to a subject a therapeutically effective amount of tau to a subject, the ... The peptide reduces the amount of tau in the subject's plasma by at least about 95%.

[0158] In yet another aspect, there is provided a method of attenuating tau protein activity in a cell, comprising the steps of: Provided herein are methods for treating a pulmonary edema, comprising contacting said cells with a peptide provided herein. In yet another aspect, a method of attenuating tau protein activity in a subject comprises administering to said subject administering to the subject an effective amount of a peptide provided herein or a pharmaceutical composition comprising same. Provided herein are methods comprising: Thus, in some embodiments, the present invention provides The peptides that are produced attenuate (e.g., partially attenuate) tau protein-induced signaling. A non-limiting example of a tau protein activity is its ability to bind tau to stabilize microtubules. Interacting with tubulin to form helices and / or straight filaments , activation of inflammatory signaling pathways, and impaired insulin signaling in the brain. .

[0159] In some embodiments, the peptides provided herein inhibit tau protein in cells. Attenuates activity (e.g., tau protein-induced signaling) by at least about 10%. In some embodiments, the peptides provided herein inhibit tau protein activity in cells (e.g., For example, it attenuates tau protein-induced signaling by at least about 20%. In embodiments, the peptides provided herein inhibit tau protein activity in cells (e.g., In some embodiments, the tau protein-induced signal transduction is attenuated by at least about 30%. In this regard, the peptides provided herein are intended to inhibit tau protein activity in cells (e.g., tauta In some embodiments, the method further comprises attenuating expression of the IL-1 protein by at least about 40%. The peptides provided herein are useful for inhibiting tau protein activity in cells (e.g., tau protein activation). In some embodiments, the present invention attenuates the expression of a phosphodiesterase (PDS)-induced signaling by at least about 50%. The peptides provided herein are intended to inhibit tau protein activity in cells (e.g., tau protein induction). In some embodiments, the method of the present invention provides a method for reducing the amount of signal transduction that occurs during cell death by at least about 60%. The peptides provided may be used to inhibit tau protein activity in cells (e.g., tau protein-induced signal transduction). In some embodiments, the method provided herein attenuates the transmission of radiation (radiation) by at least about 70%. The peptides inhibit tau protein activity in cells (e.g., tau protein-induced signal transduction). In some embodiments, the peptides provided herein attenuate the expression level of The drug reduces tau protein activity (e.g., tau protein-induced signaling) in cells. In some embodiments, the peptides provided herein reduce the expression of cellular Inhibits intracellular tau protein activity (e.g., tau protein-induced signal transduction) by at least about 95%. % attenuation. In a specific embodiment, the cell is a retinal cell.

[0160] In some embodiments, the peptides provided herein are useful for detecting tau protein in a subject. Attenuates protein activity (e.g., tau protein-induced signal transduction) by at least about 10%. In some embodiments, the peptides provided herein are used to detect and / or treat tau protein in a subject. Attenuates activity (e.g., tau protein-induced signaling) by at least about 20%. In some embodiments, the peptides provided herein are useful for evaluating tau protein activity in a subject. (e.g., tau protein-induced signaling) by at least about 30%. In embodiments, the peptides provided herein are useful for measuring tau protein activity (e.g., For example, it attenuates tau protein-induced signaling by at least about 40%. In embodiments, the peptides provided herein are used to reduce tau protein activity (e.g., For example, the tau protein-induced signal transduction is attenuated by at least about 50%. In one embodiment, the peptides provided herein are used to reduce tau protein activity (e.g., , tau protein-induced signaling) by at least about 60%. In some embodiments, the peptides provided herein are used to treat tau protein activity (e.g., In some embodiments, the tau protein-induced signal transduction is attenuated by at least about 70%. Thus, the peptides provided herein are useful for reducing tau protein activity (e.g., tau expression) in a subject. In some embodiments, the antibody or antibody that inhibits the expression of the IL-1 protein is attenuated by at least about 80%. The peptides provided herein are useful for reducing tau protein activity (e.g., tau In some embodiments, the IL-1 protein-induced signal transduction is attenuated by at least about 90%. The peptides provided herein can be used to measure tau protein activity (e.g., tauta The antibody attenuates the expression of β-lactamase (β-lactamase) by at least about 95%.

[0161] In yet another aspect, there is provided a method of treating or preventing a disease or disorder in a subject, comprising: administering to the subject a therapeutically effective amount of a peptide provided herein or a pharmaceutical composition comprising the same. As used herein, a disease or disorder refers to a condition that is caused by, for example, a disease or disorder that is caused by, for example, a tumor. It also includes one or more symptoms of a disease or disorder.

[0162] In certain embodiments, the disease or disorder is an amyloid (or amyloid beta)-related disease or disorder. In certain embodiments, the disease or disorder is associated with amyloid fibril formation, aggregation or deposition. In one embodiment, the disease or disorder is a neurological disorder. In certain embodiments, the disease or disorder is a neurodegenerative disease.

[0163] In some embodiments, the disease or disorder is an ocular disorder. The disorder is associated with accumulation of amyloid beta. In some embodiments, the eye disorder is macular degeneration. In some embodiments, the eye disorder is age-related macular degeneration.

[0164] In some embodiments, the peptides of the present disclosure inhibit the formation of amyloid fibrils, regardless of the clinical setting. Administered therapeutically or prophylactically to treat a disease associated with the formation, aggregation or deposition of The peptides of the present disclosure inhibit the formation of amyloid fibrils through the following mechanisms, including but not limited to amyloid fibril formation: or slowing the rate of deposition; reducing the extent of amyloid deposition; amyloid fibril formation inhibiting, reducing, or preventing amyloid-induced inflammation; inhibiting, reducing, or preventing amyloid-induced inflammation; Enhancement of amyloid clearance; or amyloid-induced (oligomeric or fibrillar) poisons The aim of this study is to modulate the course of amyloid-β-related diseases by either protecting cells from Modulation of amyloid deposition can act in such a way as to prevent or halt amyloid formation or accumulation. and subjects with ongoing amyloidosis, e.g., subjects who already have amyloid aggregates. Inhibition or slowing of further amyloid aggregation in patients with ongoing amyloidosis The term "amyloid deficiency syndrome" is intended to encompass the reduction or reversal of amyloid aggregates in a subject. Modulation of cytidine aggregation can be achieved by, for example, administering to an untreated subject or to a treated subject prior to treatment. Subjects with cerebral amyloidosis as determined by clinically measurable improvement, For example, in subjects with Alzheimer's disease or cerebral amyloid angiopathy, stabilization of cognitive function stabilization or prevention of further decline in cognitive function (i.e., preventing, slowing, or halting disease progression) The objective of the study is to determine whether the patient is at increased risk of developing PTSD (e.g., refractory to PTSD), or ... improvement in a parameter such as Aβ or tau concentration in the CSF.

[0165] Familial or sporadic Alzheimer's disease is the predominant form of dementia in the elderly population. Other types of dementia are also seen. These include frontotemporal degeneration, which is associated with Pick's disease. , vascular dementia, senile dementia with Lewy bodies, and parkinsonism with frontal atrophy These conditions include progressive supranuclear palsy, corticobasal degeneration, and Down's syndrome-related Alzheimer's disease. Plaque formation is a common cause of infectious diseases such as CJD, scrapie and BSE. The present disclosure relates to the treatment of such neurodegenerative diseases, particularly neurotoxic protein proteins. The present invention is directed to the treatment of diseases involving larvae, such as amyloid plaques.

[0166] Down's syndrome is a serious human disorder with an incidence of 1 in 800 births. associated with the presence of an extra copy of chromosome 21 (trisomy 21) in individuals who have received The β-amyloid precursor protein (β-APP) gene is located very close to the Down syndrome locus. It is encoded on chromosome 1. All individuals with Down syndrome who survive beyond 40 years In this case, the patient develops Alzheimer's-like dementia and Aβ deposits in the brain. Therefore, overproduction of Aβ There is good reason to suggest that β-amyloid is directly related to the development of dementia in both AD and Down syndrome. Therefore, the specificity of therapeutic agents for improving the symptoms of AD may also be important. It would also be useful for improving

[0167] "Dementia" is a condition characterized by disorientation, impairment of memory, judgment, and intelligence, and shallow, unstable emotions. This refers to a general mental deterioration caused by organic or psychological factors, characterized by Dementia includes vascular dementia, ischemic vascular dementia (IVD), frontotemporal dementia (FTD), and Lewy syndrome. These include dementia of the somatic type and Alzheimer's disease. The most common form is Alzheimer's disease (AD).

[0168] The peptides provided herein can be used to treat mild cognitive impairment. Mild cognitive impairment ("MCI") is a condition that affects thinking skills that is not necessarily associated with the presence of dementia. A condition characterized by a mild but measurable state of impairment. frequently precedes Alzheimer's disease.

[0169] Furthermore, abnormal accumulation of APP and amyloid β proteins in muscle fibers is characterized by sporadic inclusions. It has been implicated in the pathology of intracellular myositis (IBM) (Askanas et al., 1996, Proc. Natl. Acad. Sci. USA 93: 1314-1319; Askanas, V. et al., 1995, Current Opinion in Rheumatology 7: 486 496). Thus, the peptides provided herein can be used to enhance delivery of peptides to muscle fibers. Treatment of disorders in which amyloid beta protein is abnormally deposited in extraneuronal locations, such as EBM with The compounds may be used prophylactically or therapeutically in the treatment of injury.

[0170] Furthermore, Aβ accumulates along the basal surface of the retinal pigment epithelium in individuals with age-related macular degeneration (ARMD). It has been shown to be associated with the accumulation of abnormal extracellular deposits known as drusen, which ARMD is a cause of irreversible visual loss in the elderly. Aβ deposition is thought to be a cause of retinal pigment epithelium. It is believed that epithelial atrophy, drusen formation, and local inflammatory events contribute to the pathogenesis of ARMD. It is believed that this may be the case (Johnson et al., 2002, Proc. Natl. Acad. Sci. USA 99(18), 11830-5).

[0171] Thus, the present disclosure provides a method for treating an amyloid-related disease or disorder in a subject, preferably a human. The present invention relates to a method for treating or preventing damage to a subject, the method comprising the steps of: and administering a therapeutic amount of a peptide provided herein such that the cytotoxicity or cytotoxicity of the peptide is reduced or inhibited. In another embodiment, the present disclosure relates to a method comprising administering to a subject (preferably The present invention relates to a method for treating or preventing an amyloid-related disease in a subject (e.g., a human) comprising: Improved or stabilized cognitive function or further deterioration is due to cerebral amyloidosis, e.g. For example, prognosis may improve in patients with Alzheimer's disease, Down's syndrome, or cerebral amyloid angiopathy. A therapeutic amount of a peptide provided herein is administered to the subject so as to prevent, slow, or stop the progression of the disease. The present invention relates to a method comprising:

[0172] In certain embodiments, the disease or disorder is Parkinson's disease (PD), Alzheimer's disease (AD), or alveolar nephropathy. A group consisting of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or dementia. In one embodiment, the disease or disorder is Parkinson's disease. In one embodiment, the disease or disorder is traumatic brain injury. Amyotrophic lateral sclerosis. In one embodiment, the disease or disorder is multiple sclerosis. In certain embodiments, the disease or disorder is dementia.

[0173] In one embodiment, the disease or disorder is frontotemporal dementia, a condition previously associated with Pick's disease. Temporal degeneration, vascular dementia, corticobasal degeneration, ischemic vascular dementia (IVD), Dementia or cognitive impairment selected from the group consisting of dementia with B bodies and Alzheimer's disease Dementia-related disease or disorder.

[0174] In some embodiments, the disease or disorder is an ocular disorder. Or the condition is Down's Syndrome.

[0175] In one embodiment, the disease or disorder is a transmissible spongiform encephalopathy (scrapie in sheep, scrapie in humans, Leutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), etc.), cerebral amyloid angiopathy , hereditary cerebral hemorrhage with amyloidosis, mild cognitive impairment, sporadic inclusion body myositis and age-related jaundice The macular degeneration is selected from the group consisting of

[0176] In one embodiment, the disease or disorder is Alzheimer's disease. Zheimer's disease is stage 1 AD (no damage). The disease is stage 2 AD (very mild decline). In one embodiment, the Alzheimer's disease is In one embodiment, the Alzheimer's disease is stage 4 In one embodiment, the Alzheimer's disease is stage 5 AD (moderate decline). In one embodiment, the Alzheimer's disease is stage 6 AD (severe impairment of the brain function, neurodegenerative disorders, and neurodegenerative diseases). In one embodiment, the Alzheimer's disease is stage 7 AD (very severe and progressive decline). (a drastic decline).

[0177] In certain embodiments, the disorder, disease, or condition is a disorder mediated by tau protein. In one embodiment, the disorder is a disorder mediated by tau protein, The disease or condition is a tauopathy. In one embodiment, the disease or condition is mediated by tau protein. The mediated disorder, disease or condition is Alzheimer's disease.

[0178] The methods provided herein encompass treating subjects regardless of the patient's age, although However, some diseases or disorders are more prevalent in certain age groups.

[0179] Depending on the disease to be treated and the condition of the subject, the peptides provided herein or those containing same may be used. The pharmaceutical compositions, including those described herein, may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, CIV, intracisternally, or by injection or administration by any suitable route). or by injection, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (topi The composition can be administered by any route of administration, such as transdermal or local. The peptides provided herein or pharmaceutical compositions containing same may be administered alone or in suitable dosage units. and , pharma- ceutical acceptable excipients, carriers, adjuvants and vehicles suitable for each administration route. Details on administration and dosing are provided in Section 5.6 below. .

[0180] However, the specific dose level and dosing frequency for any particular subject can vary and may be used. The activity of the specific peptide, the metabolic stability and duration of action of the peptide, age, weight, General health, sex, diet, mode and frequency of administration, rate of excretion, drug combinations, specific illnesses It will be understood that the outcome will depend on a variety of factors, including the severity of the condition, as well as the host being treated. .

[0181] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human.

[0182] The peptides provided herein or pharmaceutical compositions comprising same are useful for treating the disorders described herein. in combination with other therapeutic agents useful in the treatment and / or prevention of an injury, disease, or condition; can also be used in combination.

[0183] As used herein, the term "combination" refers to the use of two or more therapeutic agents (e.g., one or more prophylactic agents and However, use of the term "in combination" includes the use of a therapeutic agent (e.g., There are no limitations on the order in which prophylactic and / or therapeutic agents are administered to a subject with a disease or disorder. A first therapeutic agent (e.g., a prophylactic or therapeutic agent, such as a peptide provided herein) may be administered in combination with a second Prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks , 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to, at the same time as, or thereafter ( For example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours. 1 hour, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks Therapeutic methods may be administered to a subject after (after) administration of the compound of formula (I). Triple therapy is also contemplated herein.

[0184] In some embodiments, the route of administration of the peptides provided herein or pharmaceutical compositions comprising the same. The pharmaceutical composition is independent of the route of administration of the second therapeutic agent. The provided peptide or a pharmaceutical composition comprising same is administered orally. The peptides provided herein or pharmaceutical compositions containing same are administered intravenously. In accordance with these embodiments, the peptides provided herein or pharmaceutical compositions comprising same are is administered orally or intravenously, and the second therapeutic agent is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, intravenously, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, via liposomes, by inhalation, intravaginally, intraocularly By local delivery using a catheter or stent, the drug can be delivered subcutaneously, intrafatally, intraarticularly, or intrathecally. In one embodiment, the compositions provided herein may be administered in a sustained release or sustained release form. The peptide or a pharmaceutical composition containing the same and the second therapeutic agent are administered by the same administration mode. In another embodiment, the peptides provided herein are administered orally or by IV. The drug or a pharmaceutical composition containing it can be administered by one mode of administration, for example, by IV. However, the second agent is administered by a different mode of administration, for example orally.

[0185] In certain embodiments, each method provided herein independently further comprises administering to a patient a second therapeutic agent. The method may include administering

[0186] 5.6 Methods of Administration and Dosage In a specific embodiment, the present invention provides a method for the prevention and / or treatment of a disease or condition. Provided herein are compositions comprising the peptides provided herein. In one embodiment, the peptides are A composition for use in the prevention of a disease or condition, comprising a peptide as provided herein. In one embodiment, a composition is provided for use in treating a disease or condition. The composition for administering the present invention comprises a peptide as provided herein. In certain embodiments, the disease or disorder is amyloid (or amyloid-β) associated. In certain embodiments, the disease or disorder is amyloid fibril formation, aggregation or In some embodiments, the disease or disorder is a neurological disease. In one embodiment, the disease or disorder is a neurodegenerative disease. The disease or disorder is Parkinson's disease (PD), Alzheimer's disease (AD), traumatic brain injury (TBI), muscle amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or dementia. In some embodiments, the disease or disorder is frontotemporal dementia, frontal lobe associated with Pick's disease. Cephalic degeneration, vascular dementia, corticobasal degeneration, ischemic vascular dementia (IVD), Lewy dementia Dementia or dementia selected from the group consisting of dementia with corpus callosum and Alzheimer's disease In some embodiments, the disease or disorder is an eye disorder. In embodiments, the eye disorder is macular degeneration. In some embodiments, the eye disorder is age-related macular degeneration. In one embodiment, the disorder, disease, or condition is Down's Syndrome. The disease or disorder is a transmissible spongiform encephalopathy (scrapie in sheep, Creutzfeldt-Jakob disease in humans). Chronic JD (CJD), bovine spongiform encephalopathy (BSE), cerebral amyloid angiopathy, amyloidosis Hereditary cerebral hemorrhage, mild cognitive impairment, sporadic inclusion body myositis, and age-related macular degeneration. It is selected.

[0187] In some embodiments, the subject is a subject in need thereof. In another embodiment, the subject is at risk of having a disease or condition. In some embodiments, administration is for the prevention, management, treatment, or amelioration of a disease or condition. Bringing good.

[0188] In one embodiment, the composition is for use in the prevention and / or treatment of symptoms of a disease or condition. Provided herein are compositions comprising the peptides provided herein. In embodiments, the composition is for use in the prevention of symptoms of a disease or condition, comprising the Provided herein are compositions comprising the peptides provided herein. In one embodiment, the peptides are A composition for use in treating a symptom of a disease state, comprising a peptide as provided herein. Provided herein is a composition comprising: (or amyloid β)-related disease or disorder. In one embodiment, the disease or disorder is The disease or disorder is associated with amyloid fibril formation, aggregation or deposition. In one embodiment, the disease or disorder is a neurological disease. In one embodiment, the disease or disorder is a neurodegenerative disease. In one embodiment, the disease or disorder is Parkinson's disease (PD), Alzheimer's disease (ALD), D) from traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or dementia In certain embodiments, the disease or disorder is selected from the group consisting of frontotemporal dementia, Pick's disease, Frontotemporal degeneration, vascular dementia, corticobasal degeneration, and ischemic stroke are associated with vascular dementia (IVD), dementia with Lewy bodies, and Alzheimer's disease. In one embodiment, the disease or disorder is a dementia or dementia-related disease or disorder selected from the group consisting of In some embodiments, the eye disorder is macular degeneration. The disorder is age-related macular degeneration. In one embodiment, the disorder, disease, or condition is Down's syndrome. In certain embodiments, the disease or disorder is a transmissible spongiform encephalopathy (scrapie in sheep, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), etc., cerebral amyloid angiopathy damage, hereditary cerebral hemorrhage with amyloidosis, mild cognitive impairment, sporadic inclusion body myositis and aging macular degeneration.

[0189] In some embodiments, the subject is a subject in need thereof. In another embodiment, the subject is at risk of having a disease or condition. In some embodiments, administration results in prevention or treatment of a symptom of a disease or condition. Glass.

[0190] In another embodiment, the present invention relates to a method of preventing and / or treating a disease or condition in a subject. The method comprises administering an effective amount of a peptide as provided herein to a subject. In one embodiment, a method of preventing a disease or condition in a subject is provided, comprising administering to a subject a therapeutically effective amount of the compound described herein. Provided herein are methods that include administering an effective amount of a peptide as provided herein. In embodiments, a method of treating a disease or condition in a subject comprises administering to a subject a therapeutically effective amount of any of the methods provided herein. Provided herein are methods for treating a patient suffering from atopic dermatitis, the methods comprising administering an effective amount of a peptide comprising administering to the patient a therapeutically ... Preferably, the disease or disorder is an amyloid (or amyloid β)-related disease or disorder. In embodiments, the disease or disorder is a disease associated with amyloid fibril formation, aggregation or deposition. In some embodiments, the disease or disorder is a neurological disease. In some embodiments, the disease or disorder is a neurodegenerative disease. Son's disease (PD), Alzheimer's disease (AD), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), In one embodiment, the disease or disorder is selected from the group consisting of myelofibrosis (MF), myelofibrosis (SC), myelofibrosis (OS), myelofibrosis (CD), myelofibrosis (HFC), myelofibrosis (IT ...MF), myelofibrosis (CD), myelofibrosis (ST), myelofibrosis (ST), myelofibrosis (ST), myelofibrosis ( Harm may be caused by frontotemporal dementia, frontotemporal degeneration associated with Pick's disease, vascular dementia, Corticobasal degeneration, ischemic vascular dementia (IVD), dementia with Lewy bodies, and Alzheimer's disease Dementia or dementia-related disease or disorder selected from the group consisting of: In some embodiments, the disease or disorder is an eye disorder. In some embodiments, the eye disorder is macular degeneration. In one embodiment, the ocular disorder is age-related macular degeneration. The disease or condition is Down's syndrome. In one embodiment, the disease or disorder is transmissible cavernous idiopathic leukemia. Encephalopathy (scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle) SE), cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, mild cognitive impairment In some cases, the retinal lesions are selected from the group consisting of retinal lesions, sporadic inclusion body myositis, and age-related macular degeneration.

[0191] In some embodiments, the subject is a subject in need thereof. In another embodiment, the subject is at risk of having a disease or condition. In some embodiments, the administration results in the prevention or treatment of a disease or condition.

[0192] In another embodiment, the present invention relates to a method for preventing and / or treating a symptom of a disease or condition in a subject. The method comprises administering an effective amount of a peptide as provided herein. In one embodiment, a method for preventing a symptom of a disease or condition in a subject is provided. The method comprises administering an effective amount of a peptide as provided herein. In one embodiment, a method of treating a symptom of a disease or condition in a subject is provided, comprising: Provided herein are methods for treating a patient suffering from atopic dermatitis, the methods comprising administering an effective amount of a peptide provided herein. In certain embodiments, the disease or disorder is an amyloid (or amyloid beta) associated disease. In certain embodiments, the disease or disorder is amyloid fibril formation, aggregation or precipitation. In one embodiment, the disease or disorder is a neurological disease. In some embodiments, the disease or disorder is a neurodegenerative disease. or the disorder is Parkinson's disease (PD), Alzheimer's disease (AD), traumatic brain injury (TBI), muscle atrophy The disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or dementia. In an embodiment, the disease or disorder is frontotemporal dementia, frontotemporal dementia associated with Pick's disease, Degeneration, vascular dementia, corticobasal degeneration, ischemic vascular dementia (IVD), Lewy bodies dementia or dementia-related selected from the group consisting of dementia of the idiopathic type and dementia of the Alzheimer's type In some embodiments, the disease or disorder is an eye disorder. In some embodiments, the eye disorder is macular degeneration. In some embodiments, the eye disorder is age-related macular degeneration. In some embodiments, the disorder, disease, or condition is Down's syndrome. Disorders include transmissible spongiform encephalopathies (scrapie in sheep, Creutzfeldt-Jakob disease in humans (CJD) D), bovine spongiform encephalopathy (BSE) in cattle, cerebral amyloid angiopathy, genetic disorders associated with amyloidosis cerebral hemorrhage, mild cognitive impairment, sporadic inclusion body myositis, and age-related macular degeneration. do.

[0193] In some embodiments, the subject is a subject in need thereof. In another embodiment, the subject is at risk of having a disease or condition. In some embodiments, administration also results in prevention or treatment of a symptom of a disease or condition. Drop.

[0194] A medicament comprising an effective amount of a peptide provided herein or a peptide provided herein Methods of preventing and / or treating a disease or condition by administering a composition to a subject Also provided herein are peptides that are substantially purified (i.e. (Substantially free of substances that limit its effectiveness or produce undesirable side effects). The subjects to which the therapeutic agent is administered are non-primates (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or primates. The subject may be a mammal, such as a protozoan (e.g., a monkey, such as a cynomolgus monkey, or a human). In another embodiment, the subject is a human. In another embodiment, the subject is a human having a disease or condition. do.

[0195] Various delivery systems are known, including encapsulation in liposomes, microparticles, and capsules, recombinant cells capable of expressing peptides, receptor-mediated endocytosis (Wu and Wu , 1987, J. Biol. Chem. 262:4429-4432), retroviruses or other vectors. and the like. For example, the peptides provided herein can be used to administer prophylactic or or methods of administering therapeutic agents (e.g., peptides provided herein) or pharmaceutical compositions These include parenteral (e.g., intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous), epidural, and mucosal. (e.g., intranasal and oral routes). In embodiments, prophylactic or therapeutic agents (e.g., peptides provided herein), or medicaments. The compositions are administered intranasally, intramuscularly, intravenously, or subcutaneously. The compositions can be administered to the epithelium or mucosa by any convenient route, for example, by infusion or bolus injection. By absorption through membrane linings (e.g., oral mucosa, nasal mucosa, rectal and intestinal mucosa, etc.) The composition may be administered in combination with other bioactive agents. Administration may be systemic or local. Pulmonary administration can also be by use of an inhaler or nebulizer and with an aerosolizing agent. For example, formulations such as those described in U.S. Patent Nos. 6,019,968, 5,985,320, and 5,985,320 may also be used. No. 5,985,309, No. 5,934,272, No. 5,874,064, No. 5,855,913, No. 5,290,540 , and 4,880,078; and PCT Publications WO 92 / 19244, WO 97 / 32572, WO 97 / 44013, WO 98 / No. 3,31346, and WO 99 / 66903, each of which is incorporated herein by reference in its entirety. is incorporated into.

[0196] In specific embodiments, the prophylactic or therapeutic agents, or pharmaceutical compositions provided herein are administered in a It may be desirable to administer the drug locally to the area in need of treatment. However, by local injection, by topical administration (e.g., by intranasal spray), This can be achieved by injection or by implant, which is Porous, non-porous, or gelatin containing membranes, such as sialastic membranes, or fibers In some embodiments, when administering the peptides provided herein, In this case, care must be taken to use materials to which the peptides do not absorb.

[0197] In another embodiment, the prophylactic or therapeutic agent or composition provided herein is administered in a vesicle comprising: In particular, it can be delivered in liposomes (Langer, 1990, Science 249:1527-1533; Liposomes in the Therapy of Infectious Diseases and Cancer Treat et al., in J. Immunol. 1989, pp. 353-365; Lopez-Berestein, ibid. above, pp. 317-327; see generally ibid.).

[0198] In another embodiment, the prophylactic or therapeutic agents, or compositions provided herein are administered in a controlled release form. In one embodiment, the pump can deliver the drug in a controlled release or sustained release system. can be used to achieve sustained release (Langer, supra; Sefton, 1987, C RC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al., 1980, Surgery 88:507; Saudek (See, e.g., W. et al., 1989, N. Engl. J. Med. 321:574). In another embodiment, the polymeric material is A prophylactic or therapeutic agent (e.g., a peptide provided herein) or a combination provided herein can be used to achieve controlled or sustained release of the composition (Langer and Wise, eds. ) literature, 1974, Medical Applications of Controlled Release; Sm Olen and Ball (eds.), 1984, Controlled Drug Bioavailability, Pharmaceutical Products. Design and Performance (Controlled Drug Bioavailability, Drug Product Design and Performance; Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; Le During et al., 1989, Ann. Neurol. 25:351; Hovy et al., 1985, Science 228:190; Ward et al., 1989, J. Neurosurg. 7 1:105; U.S. Patent Nos. 5,679,377; 5,916,597; PCT Publication Nos. 5,912,015; 5,989,463; 5,128,326; PCT Publication No. WO 99 / 15154; and PCT Publication No. (See O 99 / 20253.) Examples of polymers used in sustained release formulations include poly(2-hydroxybutyric acid), ... ethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene Poly(vinyl acetate), poly(methacrylic acid), polyglycolide (PLG), polyanhydride, poly(N-vinyl poly(vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol) poly(lactide-co-glycolide) (PLGA), poly(orthoester) (PLA), poly(lactide-co-glycolide) (PLGA), and poly(orthoester) (PLA). In one embodiment, the sustained release formulation is The polymers are inert, free of leachable impurities, storage stable, sterile, and biodegradable. In yet another embodiment, the controlled release or sustained release system is in the vicinity of the therapeutic target. i.e., placed in the nasal cavity or lungs, thus requiring only a fraction of the systemic dose. (Goodson, Medical Applications of Controlled Release) d Release), supra, Vol. 2, pp. 115-138 (1984). Controlled release systems are described in Langer (1990, Any of the above known to those of skill in the art may be used. The techniques can be used to produce sustained release formulations comprising one or more of the peptides provided herein. (U.S. Pat. No. 4,526,938, PCT Publication WO 91 / 05548, PCT Publication WO 96 / 20698; Ning et al. , 1996, Radiotherapy & Oncology 39:179-189; Song et al., 1995, PDA Journa of Pharmaceutical Science & Technology 50:372-397; Cleek et al., 1997, Proc. I nt'l. Symp. Control. Rel. Bioact. Mater. 24:853-854, and Lam et al., 1997, Proc. c. See Int'l. Symp. Control Rel. Bioact. Mater. 24:759-760, and these each of which is incorporated herein by reference in its entirety.

[0199] In specific embodiments, the compositions provided herein are used as prophylactic or therapeutic agents (e.g., When the nucleic acid is a nucleic acid encoding a peptide provided herein or a parent peptide thereof, the nucleic acid The acid may be constructed as part of a suitable nucleic acid expression vector, e.g., a retroviral vector. by the use of a microinjector (see U.S. Pat. No. 4,980,286), by direct injection, or by microparticle By using a gun (e.g., a gene gun; Biolistic, Dupont) to deliver it into the cells or coated with lipids or cell surface receptors or transfection agents. Or, it is administered in combination with a homeobox-like peptide known to be transported to the nucleus. (See Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868.) Thus, it is administered in vivo to promote expression of the encoded prophylactic or therapeutic agent. Alternatively, the nucleic acid can be introduced into the cell and expressed by homologous recombination in the host cell. It can be incorporated into cellular DNA.

[0200] In specific embodiments, the compositions provided herein comprise one, two or more of the compositions provided herein. In another embodiment, the compositions provided herein comprise one or more peptides. One, two or more of the peptides provided herein and In one embodiment, the agent is a prophylactic or therapeutic agent other than a medicament for preventing a disease or condition. known to be useful or used for the management, treatment and / or amelioration of In addition to the prophylactic or therapeutic agents provided herein, The composition may also include an excipient.

[0201] The compositions provided herein are pharmaceutical compositions that can be used to prepare unit dosage forms (e.g., For example, compositions suitable for administration to a subject or patient, including bulk drug compositions useful in the manufacture of pharmaceutical compositions. In one embodiment, the compositions provided herein are pharmaceutical compositions. The composition may be administered in a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., as provided herein). or other prophylactic or therapeutic agent), and a pharma- ceutical acceptable excipient. The pharmaceutical composition can be formulated to be suitable for the route of administration to a subject.

[0202] In specific embodiments, the term "excipient" also refers to a diluent, adjuvant (e.g., It can refer to an int-adjuvant (complete or incomplete) or a vehicle. Pharmaceutical excipients Water and oils, petroleum oils such as peanut oil, soybean oil, mineral oil, sesame oil, animal oils, vegetable oils, or It may be a sterile liquid, including oils of synthetic origin. Water may be used when the pharmaceutical composition is administered intravenously. Exemplary excipients are saline solution and aqueous dextrose and glycerol solution. It can also be used as a liquid excipient, especially for injectable solutions. starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chili powder, etc. Yoke, silica gel, sodium stearate, glycerol monostearate, talc , sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol The composition may optionally contain minor amounts of wetting or emulsifying agents, or These compositions may also contain pH buffering agents. It can take the form of tablets, pills, capsules, powders, sustained release formulations, etc. Oral Formulations Contains pharmaceutical grade mannitol, lactose, starch, and magnesium stearate. Contains standard excipients such as sodium saccharin, cellulose, and magnesium carbonate. Examples of suitable pharmaceutical excipients can be found in Remington's Pharmaceutical Sciences. ences (1990) Mack Publishing Co., Easton, PA. The compound may be mixed with suitable excipients in a refined form to provide a suitable form for administration to a patient. and a peptide as provided herein, such as in a therapeutically effective amount. The formulation should suit the mode of administration.

[0203] In one embodiment, the composition is adapted for intravenous administration to humans in accordance with routine procedures. Typically, compositions for intravenous administration are formulated in a sterile, isotonic aqueous buffer. Optionally, the composition also contains a solubilizing agent and a medicament to reduce pain at the site of injection. It may contain a local anesthetic such as lignocaine for relief. Such compositions may be administered by routes other than intravenous.

[0204] Generally, the components of the compositions provided herein are presented in unit dosage form, e.g., indicating the amount of active agent. as a lyophilized powder or water-free concentrate in a sealed container such as an ampoule or sachet If the composition is to be administered by injection, Can be dispensed using an infusion bottle containing pharmaceutical grade sterile water or saline When the composition is to be administered by injection, the ingredients can be mixed prior to administration. For example, an ampoule of sterile water for injection or saline can be provided.

[0205] The peptides provided herein may be packaged in a container, such as an ampoule or sachet indicating the amount of peptide. In one embodiment, the peptide can be packaged in a sealed container. The composition may be provided as a dry, sterilized, lyophilized powder or water-free concentrate, e.g. It can be reconstituted with water or saline to the appropriate concentration for administration. The peptides can be stored at 2-8°C in their original containers and the peptides can be diluted for 6 hours after reconstitution. The drug can be administered within 12 hours, such as within 12 hours, within 5 hours, within 3 hours, or within 1 hour. In an alternative embodiment, the peptides provided herein are indicative of the amount and concentration of the peptide. It is supplied in liquid form in a sealed container.

[0206] The compositions provided herein can be formulated in a neutral or salt form. Pharmaceutically acceptable salts include those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc. Those formed with anions such as sodium, potassium, ammonium, calcium, etc. amine, iron hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, These include those formed from cations such as those derived from histidine, procaine, etc. .

[0207] A prophylactic or therapeutic agent (e.g., a compound according to the present invention) that is effective in preventing and / or treating a disease or pathology. The amount of the peptide provided herein, or the composition provided herein, may be measured according to standard clinical techniques. In addition, in vitro assays can be used to determine optimal This may be used to help identify the exact dosage range to be used in the formulation. The amount will also depend on the route of administration, and the seriousness of the disease or condition, and will be determined according to the judgment of the practitioner and each patient's circumstances. The decision should be made based on the following:

[0208] Effective doses can be derived from dose-response curves derived from in vitro or animal model test systems. It can be deduced from

[0209] In certain embodiments, the route of administration of a dose of a peptide provided herein to a patient is intranasal. Intravenous, intramuscular, intravenous, or a combination thereof, but other routes as described herein are also permissible. Each dose may or may not be administered by the same route of administration. In some embodiments, the peptides provided herein are similar to those provided herein. via multiple routes of administration, either simultaneously or subsequently with the same or different peptides at doses of It can be done.

[0210] In certain embodiments, the peptides provided herein are administered prophylactically or therapeutically to a subject. The peptides provided herein are useful for preventing, reducing, or ameliorating a disease or symptom thereof. The compound can be administered prophylactically or therapeutically to a subject to inhibit or reduce the activity of the compound.

[0211] (5.7 kit) The peptides provided herein may also be delivered as articles of manufacture using packaging materials well known to those of skill in the art. Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include blister packs, bottles, tubes, Inhalers, pumps, bags, vials, containers, syringes, and selected formulations and intended administration These include, but are not limited to, any packaging material appropriate for the mode of administration and treatment.

[0212] In one embodiment, when used by a medical practitioner, the appropriate amount of active ingredient is administered to a subject. Also provided herein are kits that can simplify administration of the compounds provided herein. The provided kit includes a container of the peptide provided herein or a pharmaceutical composition containing the same, and Includes dosage form.

[0213] In certain embodiments, the kit comprises one or more other therapeutic agent(s) described herein. A container containing a dosage form of a peptide provided herein or a pharmaceutical composition containing the same in the container. include.

[0214] The kits provided herein may further include a device used to administer the active ingredient. Examples of such devices include syringes, needleless injector drips, etc. These include, but are not limited to, pouches, patches, and inhalers. The kit may also include a condom for administration of the active ingredient.

[0215] The kits provided herein can further be used to administer one or more active ingredients. For example, the composition may be reconstituted for parenteral administration and may contain a pharma- ceutical acceptable vehicle. If the active ingredient is provided in a solid form that must be dissolved, the kit may include a A suitable vehicle that can be used to form a particulate-free, sterile solution suitable for parenteral administration. Examples of pharma- ceutical acceptable vehicles include sealed containers of Water USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose Injection, include, but are not limited to, Sodium Chloride Injection, and Lactated Ringer's Injection. Ethyl alcohol, polyethylene glycol, and polypropylene Water-miscible vehicles, including, but not limited to, glycols; as well as corn oil, cottonseed oil, , peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzoic acid Non-aqueous vehicles include, but are not limited to, benzyl stomach.

[0216] For the sake of brevity, certain abbreviations are used herein. An example is the amino acid residues: The amino acids and their corresponding three-letter and one-letter abbreviations are as follows: Cage: [Table 1]

[0217] The present invention is generally described in the present specification using positive language to describe the various embodiments. The invention also relates to specific substances or materials, process steps and conditions, processes, Implementations in which certain subject matter, such as protocols, procedures, assays or analyses, is completely or partially excluded Therefore, the present invention is not limited to the above-mentioned embodiments, which are generally described herein in terms of what the present invention does not include. Although not explicitly depicted, aspects not expressly included in the present invention are nevertheless included in the present invention. Disclosed in the specification.

[0218] 6. Working Examples The following is a description of the various methods and materials used in this study and the methods for making and using the invention. This disclosure is provided so as to provide those of ordinary skill in the art with a complete disclosure and description of how to use the present invention. It is not intended to limit the scope of what the inventors regard as their invention, and the experiments below have been performed and are not intended to limit the scope of what the inventors regard as their invention. The examples given in this paper are not intended to represent all possible experiments that may be performed. The illustrative description is not necessarily implemented, but rather is consistent with the teachings of the present invention. It should be understood that explanations may be given to generate data, etc. Although efforts have been made to ensure accuracy with respect to information (e.g., amounts, percentages, etc.), , some experimental errors and deviations need to be taken into account.

[0219] 6.1 Example 1 - Generation of Variants of the P8 Peptide The P8 peptide and its variants were synthesized by solid-phase peptide synthesis. The resin was prepared by using dimethyloxybenzyl alcohol resin (Wang resin). Amino acids were bound as 9-fluorenylmethoxycarbonyl (Fmoc)-derivatives (Nova Biochem). The tert-butyl group was applied as a side-chain protecting group. For 8M2 and 8M2D, 20% Acetylation modification was performed by adding acetic anhydride solution to the resin. and 8M2D, azabenzotriazole tetramethyluronidium hexafluorophosphate. Amidation was carried out by adding HATU and diisopropylethylamine (DIPEA). After synthesis was complete, the peptide was removed from the resin. The crude product was purified by HPLC on a reversed-phase column (RP-HPLC) to >98% purity prior to use. Purification was carried out by high performance liquid chromatography. Table 1. Peptide sequences of P8 and its mutant peptides [Table 2] Note: -NH2 means C-terminal amide (-CONH2); Ac means N-terminal acetylation; d means D-acetylation It means amino acid.

[0220] 6.2 Example 2 - Metabolic stability of peptides in fresh human plasma P8, 8M1, and 8M1D were produced according to Example 1 with purities ranging from 98.0% to 99.0%. Prepare 1.00 mM primary stock solutions in acetonitrile or acetonitrile: A 0.200 mM working stock was prepared in either acetonitrile:water (1:1, v / v) or acetonitrile:water (1:1, v / v). The primary stock solution was prepared from a 1:1, v / v solution and used for the reaction. The stock solution should be stored at -20°C when not in use and kept for as short a time as possible when in use. Fresh human plasma was purified by adding sodium heparin as an anticoagulant. and maintained by.

[0221] The incubation procedure consisted of adding 5.00 μL of 0.2 mM (working stock solution) of the different peptides to Incubation began when 0.995 mL of fresh human plasma was added to a 1.7 mL snap tube. At 3, 8, and 24 hours after incubation, duplicate 50.0 μL aliquots of plasma were removed and the reaction was stopped. The incubation was terminated by placing the samples in an extraction tube containing 150 μL of methanol, which acts as a saturation agent. For each time point, an aliquot was immediately extracted by vortex mixing and centrifugation. The resulting supernatant was stored in high performance liquid chromatography (HPLC) vials, and all samples were was extracted and then analyzed by LC / MS / MS. Valacyclovir was used as a positive control.

[0222] LC / MS / MS analysis of the incubation solution was performed using a chromatographic detector prior to detection by mass spectrometry. The LC / MS system was a TQS-Micro. The assay consisted of an HPLC coupled with a HPLC Quattro Premier (Waters, Milford, MA). Heated nitrogen with Z-spray source / interface set to electrospray in positive ionization mode for peptides. The mobile phase was nebulized using a nebulizer. Ionized peptides were analyzed by Tandem Quadropole mass spectrometry (MS / MS Detection was performed using a 350 nm NMR spectrometer (S). Data was acquired using MassLynx (Waters, Milford, Mass.).

[0223] HPLC of the peptides and valacyclovir controls was performed without a guard column at a flow rate of 0.3 mL / min. The column temperature was 40°C, and the autosampler temperature was 10°C. The peptide column was a MacMod A The column was a Waters Atlantis T CE 2 Excel C18PFP, 100 x 2.1-mm, 2.0 μm column. 3, 150 × 2.1-mm, 5.0 μm. The injection loop and volume of peptide were 50.0 μL and and 20.0 μL, and the control injection loops and volumes were 20.0 μL and 2.00 μL. For the mass spectrometer for the valacyclovir control, the source temperature was set to 150°C, and the desolvation The temperature was set to 350 °C and the polarity was set to positive mode for electrospray ionization. Other HPLC and mass spectrometer parameters are given in Tables 2.1, 2.2 and 3 below. Table 2.1. HPLC Linear Gradient Program for Peptides [Table 3] Table 2.2. HPLC linear gradient program for valacyclovir [Table 4] Note: Solvent A is 0.1% formic acid in water; solvent B is 0.1% formic acid in methanol. Table 3. Mass spectrometer conditions for peptides and valacyclovir [Table 5]

[0224] The results of the LC / MS / MS analysis are summarized in Table 4 below, and show that different peptides are distinct in fresh human plasma. It was found that 8M1D was metabolized at the slowest rate, and 8M1 was metabolized at the fastest rate. Peptides P8 and 8M1D were relatively stable in fresh human plasma, with 8M1D being more stable than P8. I did. Table 4. Metabolic stability assay results for P8, 8M1, and 8M1D [Table 6]

[0225] 6.3 Example 3 - Pharmacokinetic Studies in Rats To determine the pharmacokinetics (PK) of peptides P8, 8M1D, and 8M2D in plasma and CSF, In vivo studies were performed in rats. Each peptide was administered via two routes: intravenous (IV) and subcutaneous (SC). Three rats were assigned to each dose group with each peptide. A total of 12 rats were used per study. The study design is shown in Table 5. Table 5. Pharmacokinetic study design in rats for each peptide. [Table 7]

[0226] Blood was collected via the jugular vein cannula and samples were collected in tubes with K2EDTA. After centrifugation at 4,000 x g for 5 min at 2-8°C, the resulting plasma was divided into equal aliquots. The drug was divided into 2 aliquots, frozen, and stored at -60 to -80 °C. One aliquot was for PK analysis and the other was for for Aβ analysis (see Example 4).

[0227] CSF collection was initially performed using a mixture of 80 mg / kg ketamine and 8 mg / kg xylazine at the designated The animals were anesthetized at the indicated time points (see Table 5). The depth of anesthesia was assessed by toe pinch. CSF was collected via the cisterna magna (approximately 0.05 mL), divided into equal aliquots, and frozen. The mixture was then frozen and stored at -60 to -80°C.

[0228] Both 8M1D and 8M2D had better exposure than P8 in plasma at Cmax and most time points thereafter. (See Tables 6, 7, and 8 below). Exposure was slightly higher with 8M1D than with 8M2D. Specifically, 8M1D and 8M2D were detectable in plasma for longer than P8. P6 was still detectable at 1 h and 6 h, whereas P8 was undetectable after 2 h. Table 6. Results of PK studies of P8 in rats [Table 8] Table 7. Results of PK studies of 8M1D in rats [Table 9] Table 8. Results of PK studies of 8M2D in rats [Table 10]

[0229] As shown in Tables 9, 10, and 11, both 8M1D and 8M2D exhibited excellent efficacy at Cmax and most of the time thereafter. The exposure in CSF was better with 8M2D than with 8M1D. 8M2D was also detectable in the CSF for a much longer time than P8. was still detectable at 8 hours and 8M2D was detectable at 12 hours after administration, , P8 was undetectable after 2 hours. Table 9. Results of PK studies of P8 in rats [Table 11] Table 10. Results of PK studies of 8M1D in rats [Table 12] Table 11. Results of PK studies of 8M2D in rats [Table 13]

[0230] The pharmacokinetics (PK) of peptides P8 and 8M2D were compared, specifically in plasma and CSF. The products were evaluated by two routes of administration, IV and SC. N=3 per test product per dose group. The results are shown in Figure 1. As shown in Fig. 1A to 1D, in plasma, 8M2D was at Cmax and most of the time points thereafter. 8M2D was also detectable in plasma for longer than P8 (administration at 4 and 6 hours post-dose, compared with P8, which was undetectable at 2 hours post-dose. In CSF, 8M2D had higher exposure than P8 at Cmax and most time points thereafter. D was also detectable in the CSF for a much longer period than P8 (becoming undetectable 2 hours after administration). up to 12 hours after administration, compared with P8, which showed

[0231] The pharmacokinetics (PK) of 8M2D was evaluated in various doses in transgenic mice on days 1 and 13. Further analysis was performed at a dose of 100 mg / kg / day (APPSWE (B6; SJL 2576 Kha; Taconic)). Correlated memory impairment, Aβ elevation, and amyloid plaques in transgenic mice ative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Sc ience 274:99-102 (1996); and Haugabook et al., Phosphatidylinositol Kinase in the Tg2576 animal model of Alzheimer's disease following oral administration of the enzyme inhibitor wortmannin Reduction of Abeta accumulation in the Tg2576 animal model of A lzheimer's disease after oral administration of the phosphatidyl- inositol kinas The results are shown in Table 12 and Figure 1. Shown in 2. Table 12. PK analysis of 8M2D in transgenic mice [Table 14]

[0232] 6.4 Example 4 - Efficacy of P8, 8M1D and 8M2D in lowering Aβ40 in rat plasma Rats (n=3 per peptide) were subcutaneously administered P8, 8M1D, or 8M2D (10 mg / kg) and plasma was then administered. Time points were collected at 0, 6, 12, and 24 hours and Aβ40 analysis was performed by ELISA (Invitrogen). did.

[0233] The results (see FIG. 3) show that 8M2D reduces Aβ40 levels to a greater extent. It was found to be more potent than P8 and 8M1D. Specifically, at 12 hours post-administration , 8M2D reduced Aβ40 by about 35%; whereas P8 reduced Aβ40 by about 22% and 8M1D reduced Aβ40 by about 22%. At 24 hours post-dose, 8M2D still reduced Aβ40 by approximately 27%. showed long-term effects on Aβ40 levels, more than double that of P8, which reduced Aβ40 levels by approximately 13% 8M2D was also superior to 8M1D, which reduced Aβ40 by approximately 19% at 24 hours. . Table 13. Percentage reduction of Aβ40 in plasma of rats treated with P8, 8M1D and 8M2D (Results represent the average of three rats per peptide) [Table 15]

[0234] Similar studies will be performed to analyze the efficiency of the peptides for lowering Aβ42.

[0235] 6.5 Example 5 - P8 and 8M2D Brain in Reducing Aβ in Transgenic Mice and validity of the A key component to the development of any therapeutic agent for a disease like AD is the ability to deliver it to the brain. Brain delivery and efficacy of P8 and 8M2D in lowering Aβ are discussed in Section 6 above. The analysis was performed using transgenic mice as described in .3.

[0236] As shown in 4A-4B below and in Table 14, SC administration delivered P8 and 8M2D to the APPTg mouse brain, The dose was sufficient to reduce Aβ in the brain. Specifically, the administration of P8 (Figure 4A) and 8M2D (Figure 4B) Aβ analysis in CSF of APP transgenic mice after SC administration demonstrates target engagement using , showing brain penetration and efficacy (analysis in CSF and brain). The maximally effective dose of 8M2D in this study was >50 mg / kg, which resulted in a 65% reduction in Aβ42. A five-fold increase in dose results in a slight increase in efficacy. Conduct experiments to establish. Table 14. Brain concentrations [Table 16]

[0237] 6.6 Example 6 - Reduction of Aβ in the Retina In this example, we investigated the accumulation of Aβ in the retina. The researchers differentiated retinal cells from induced pluripotent stem cells (iPSCs). The results showed that these retinal cells produced Aβ. These results show that the increase in IL-1 expression can be reduced in the presence of P8 or 8M2D.

[0238] The function of P8 and 8M2D in reducing Aβ in retinal cells from patients with age-related macular degeneration To test this, a similar experiment is performed.

Claims

1. (i) The N-terminal amino acid Asp is acetylated, and the C-terminal amino acid Leu is amidated. 【Chemistry 1】 An array of; (ii) the N-terminal amino acid Asp is a D-amino acid and the C-terminal amino acid Leu is amidated 【Chemistry 2】 or (iii) the N-terminal amino acid Asp is a D-amino acid and is acetylated, and the C-terminal amino acid Leu is an amide to be 【Chemistry 3】 Array of A peptide comprising:

2. The peptide 【Chemistry 4】 The peptide of claim 1, comprising the sequence:

3. The peptide 【Chemistry 5】 The peptide of claim 1, comprising the sequence:

4. The peptide 【Chemistry 6】 The peptide of claim 1, comprising the sequence:

5. A first domain comprising the sequence of SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5, and a second domain A peptide comprising:

6. The peptide of claim 5, wherein the second domain comprises an Fc domain.

7. The peptide of claim 5, wherein the second domain comprises a purified peptide.

8. A pharmaceutical composition comprising the peptide according to any one of claims 1 to 7 and a pharma- ceutical acceptable excipient. Pharmaceutical composition.

9. Intracellular presenilin-1 (PS-1) and / or presenilin-2 (PS-2) and β-amyloid precursor A method for attenuating the binding of a protein (β-APP) comprising the steps of: or the pharmaceutical composition of claim 8, wherein the method comprises contacting a cell with the peptide of claim 8.

10. Attenuating the production of amyloid beta in cells, attenuating amyloid beta activity, or inhibiting tau 1. A method of attenuating the production of a protein or attenuating tau protein activity, comprising: A peptide according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8, and said cells. and optionally contacting amyloid-β activity with an amyloid-β-inducing signal. and, where appropriate, tau protein activity is tau protein-induced signal transduction. The method.

11. attenuating amyloid beta production or attenuating amyloid beta activity in a subject; A method for attenuating the production of tau protein or attenuating tau protein activity. a therapeutically effective amount of the peptide according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 and optionally administering to the subject a composition comprising: Inducible signaling, and optionally, tau protein activity induces tau protein-inducible signaling. The method according to claim 1, wherein said transfer is null.

12. The method of claim 10 or 11, wherein the amyloid beta is amyloid beta 40.

13. The method of claim 10 or 11, wherein the amyloid beta is amyloid beta 42.

14. A method for treating a disease or disorder in a subject comprising administering to a subject a therapeutically effective amount of any one of claims 1 to 7.

10. The method of claim 8, further comprising administering to said subject a peptide according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 8. , the method.

15. The disease or disorder is an amyloid (or amyloid β)-related disease or disorder, Diseases or disorders associated with neurodegenerative disorders, neurodegenerative disorders, or neurofibroma 15. The method of claim 14, wherein

16. The disease or disorder is Alzheimer's disease, Parkinson's disease, traumatic brain injury, amyotrophic lateral sclerosis, 15. The method of claim 14, wherein the disease is selected from the group consisting of follicular sclerosis, multiple sclerosis, and dementia.

17. The disease or disorder is frontotemporal dementia, frontotemporal degeneration associated with Pick's disease , vascular dementia, corticobasal degeneration, ischemic vascular dementia (IVD), Lewy body dementia dementia or dementia-related disease selected from the group consisting of dementia of the 1st generation and Alzheimer's disease; 15. The method of claim 14, wherein the disease is a cancer or disorder.

18. 15. The method of claim 14, wherein the disease or disorder is an eye disorder or Down's syndrome.

19. 20. The method of claim 18, wherein the eye disorder is associated with Alzheimer's disease.

20. The eye disorder is macular degeneration, and optionally the macular degeneration is age-related macular degeneration (AMD).

20. The method of claim 18,

21. The disease or disorder is associated with transmissible spongiform encephalopathy, cerebral amyloid angiopathy, amyloidosis, Selected from the group consisting of hereditary cerebral hemorrhage, mild cognitive impairment, sporadic inclusion body myositis, and age-related macular degeneration. The method of claim 14,

22. A method for improving memory in a subject, comprising administering to said subject a therapeutically effective amount of the compound according to any one of claims 1 to 7. The method comprises administering to a subject a peptide or a pharmaceutical composition of claim 8.

23. The method according to any one of claims 11 to 22, wherein the subject is a human subject.

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