Apolipoprotein a-i mimetic peptides and methods of using

Abstract

Disclosed herein, are peptides or fragments thereof capable of binding to oxidized lipids, lipid hydroperoxides or lipopolysaccharides, and a pharmaceutical composition containing the peptides or fragments and methods of using to enhance plasma anti-oxidant PON-1 activity, reduce the risk or ameliorating symptoms of a lipid-mediated inflammatory disease or treat a lipid disorder.

Description

[0001] Attorney’s Docket No.: 21085.0193P1

[0002] APOLIPOPROTEIN A-I MIMETIC PEPTIDES AND METHODS OF USING

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 692,330, filed on September 9, 2024. The content of this earlier filed application is hereby incorporated by reference in its entirety.

[0005] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0006] This invention was made with government support under Grant Number EY06109 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0007] INCORPORATION OF THE SEQUENCE LISTING

[0008] The present application contains a sequence listing that is submitted concurrent with the filing of this application, containing the file name “21085_0193Pl_SL” which is 196,608 bytes in size, created on August 20, 2025, and is herein incorporated by reference in its entirety pursuant to 37 C.F.R. § 1.52(e)(5).

[0009] BACKGROUND

[0010] About one in three adults in the United States have high levels of low-density lipid cholesterol. Increased levels of low-density lipid cholesterol, triglycerides or both can contribute to one or more lipid disorders. Currently available treatments require repeated administration and have untoward effects. Thus, a need exists for therapies that can provide rapid benefit with fewer side effects with long-term therapeutic effects that do not require contestant administration.

[0011] SUMMARY

[0012] Disclosed herein are peptides comprising or consisting of a sequence of at least 90% identical to ammo acid sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6). DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof.

[0013] Disclosed herein are pharmaceutical compositions for reducing the risk or ameliorating one or more symptoms of a lipid-mediated inflammatory disease, the pharmaceutical compositions comprising: a) a therapeutically effective amount of a peptide Attorney’s Docket No.: 21085.0193P1 comprising or consisting of a sequence of at least 90% identical to amino acid sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof; and b) a pharmaceutically acceptable carrier.

[0014] Disclosed herein are methods of enhancing plasma anti-oxidant enzyme PON-1 activity in a subject, the methods comprising: administering to a subject a therapeutically effective amount of a peptide comprising or consisting of a sequence of at least 90% identical to amino acid sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof; and b) a pharmaceutically acceptable carrier.

[0015] Disclosed herein are methods for treating a subject with a lipid disorder, the method comprising administering to the subject an effective amount of a peptide comprising or consisting of a sequence of at least 90% identical to amino acid sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5). DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof; and b) a pharmaceutically acceptable carrier.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows peptides 2Wc4F comprising SEQ ID NO: 1 (center; and SEQ ID NO: 155) and 2Wi4F SEQ ID NO: 4 (right; and SEQ ID NO: 156) with improve efficacy. SEQ ID NO: 1 shows that the tryptophan amino acids are positioned at the center between the polar and nonpolar faces. SEQ ID NO: 4 shows that the tryptophan amino acids are positioned at the interface of the polar-nonpolar face. Peptide 4F (8) is also shown.

[0018] FIG. 2 shows results of the peptides 2Wc4F and 2Wi4F compared to 4F in the DCFDA plate assay.

[0019] FIG. 3 shows results of the peptides 2Wc4F and 2Wi4F compared to 4F in the PON-1 plate assay. Attorney’s Docket No.: 21085.0193P1

[0020] FIG. 4 shows that peptide 2Wc4F is most effective in clearing lipid hydroperoxides from septic patient plasma.

[0021] FIG. 5 shows that peptide 2Wc4F is most effective in clearing lipid hydroperoxides from LDL-receptor null mice.

[0022] DETAILED DESCRIPTION

[0023] The present disclosure can be understood more readily by reference to the following detailed description of the invention, the figures and the examples included herein.

[0024] Before the present methods and compositions are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0025] Moreover, it is to be understood that unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, and the number or t pe of aspects described in the specification.

[0026] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0027] DEFINITIONS

[0028] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Attorney’s Docket No.: 21085.0193P1

[0029] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes mixtures of compounds, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.

[0030] The word “or” as used herein means any one member of a particular list and also includes any combination of members of that list.

[0031] Ranges can be expressed herein as from “about” or “approximately” one particular value, and / or to “about” or “approximately” another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” or “approximately,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0032] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0033] As used herein, the term “sample” is meant a tissue or organ from a subject; a cell (either within a subject, taken directly from a subject, or a cell maintained in culture or from a cultured cell line); a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (e.g., a polypeptide or nucleic acid), which is assayed as described herein. A sample may also be any body fluid or excretion (for example, but not limited to, blood, urine, stool, saliva, tears, bile) that contains cells or cell components.

[0034] As used herein, the term “subject” refers to the target of administration, e.g., a human. Thus, the subject of the disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory' animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). In one aspect, a subject is a mammal. In another aspect, a subject is a human. The term does not denote a particular age or sex. Thus, Attorney’s Docket No.: 21085.0193P1 adult, child, adolescent and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.

[0035] As used herein, the term '‘patient” refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. In some aspects of the disclosed methods, the “patient” has been diagnosed with a need for treatment, such as, for example, prior to the administering step.

[0036] As used herein, the term “comprising” can include the aspects “consisting of?and “consisting essentially of.”

[0037] As used herein, the term “amino acid sequence” refers to a list of abbreviations, letters, characters or words representing amino acid residues. The amino acid abbreviations used herein are conventional one letter codes for the amino acids and are expressed as follows: A, alanine; C, cysteine; D aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, try ptophan; and Y, tyrosine.

[0038] As used herein the terms “ammo acid” and “amino acid identity” refers to one of the 20 naturally occurring amino acids or any non-natural analogues that may be in any of the antibodies, variants, or fragments disclosed. Thus “amino acid” as used herein means both naturally occurring and synthetic amino acids. For example, homophenylalanine, citrulline and norleucine are considered amino acids for the purposes of the invention. “Amino acid” also includes amino acid residues such as proline and hydroxyproline. The side chain may be in either the (R) or the (S) configuration. In some aspects, the amino acids are in the D- or L- configuration. If non-naturally occurring side chains are used, non-amino acid substituents may be used, for example to prevent or retard in vivo degradation.

[0039] ■‘Peptide” as used herein refers to any peptide, oligopeptide, polypeptide, gene product, expression product, or protein. A peptide is comprised of consecutive amino acids. The term “peptide” encompasses naturally occurring or synthetic molecules.

[0040] As used herein, “reverse oriented”, “reversed orientation”, “reverse analog” or “reverse sequence” refers to a peptide, or a portion of the peptide, has a reverse amino acid sequence as compared to a non-reverse oriented peptide (i.e., the original sequence is read (or written) from right to left). For example, if one peptide has the amino acid sequence ABCDE, its reverse analog or a peptide having its reverse sequence is as follows: EDCBA.

[0041] “Inhibit,” “inhibiting” and “inhibition” mean to diminish or decrease an activity, level, response, condition, disease, or other biological parameter. This can include, but is not Attorney’s Docket No.: 21085.0193P1 limited to, the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% inhibition or reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, in some aspects, the inhibition or reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. In some aspects, the inhibition or reduction is 10-20, 20-30, 30-40. 40-50, 50-60, 60-70. 70-80, 80-90, or 90-100% as compared to native or control levels. In some aspects, the inhibition or reduction is 0-25. 25-50, 50-75. or 75- 100% as compared to native or control levels.

[0042] “Treatment” and “treating” refer to administration or application of a therapeutic agent (e.g., a peptide or fragment thereof as described herein) to a subject or performance of a procedure or modality on a subject for the purpose of obtaining a therapeutic benefit of a disease or health-related condition. For example, a treatment may include administration of a pharmaceutically effective amount of a peptide or fragment that binds oxidized lipids, lipid hydroperoxides, or lipopolysaccharides (LPS).

[0043] As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, relieving, delaying onset of. inhibiting or slowing progression of. reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. For example, the disease, disorder, and / or condition can be lipid-mediated inflammatory disease or a lipid disorder. In some aspects, the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, PAD. cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus, or a combination thereof.

[0044] The term “fragment” can refer to a portion (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, etc. amino acids) of a peptide that is substantially identical to a reference peptide and retains the biological activity of the reference. In some aspects, the fragment or portion retains at least 50%, 75%, 80%, 85%, 90%, 95% or 99% of the biological activity of the reference peptide described herein. Further, a fragment of a referenced peptide can be a continuous or contiguous portion of the referenced polypeptide (e.g., a fragment of a peptide that is ten amino acids long can be any 2-9 contiguous residues within that peptide). Attorney’s Docket No.: 21085.0193P1

[0045] A “variant’' can mean a difference in some way from the reference sequence other than just a simple deletion of an N- and / or C-terminal amino acid residue or residues. Where the variant includes a substitution of an amino acid residue, the substitution can be considered conservative or non-conserv alive. Conservative substitutions are those within the following groups: Ser, Thr, and Cys; Leu, ILe, and Vai; Glu and Asp; Lys and Arg; Phe, Tyr, and Trp; and Gin, Asn, Glu, Asp, and His. Variants can include at least one substitution and / or at least one addition, there may also be at least one deletion. Variants can also include one or more non-naturally occurring residues. For example, they may include selenocysteine (e.g., seleno-L- cysteine) at any position, including in the place of cysteine. Many other “unnatural'’ amino acid substitutes are known in the art and are available from commercial sources. Examples of non-naturally occurring amino acids include D-amino acids, amino acid residues having an acetylaminomethyl group attached to a sulfur atom of a cysteine, a pegylated amino acid, and omega amino acids of the formula NH2(CH2)nCOOH wherein n is 2-6 neutral, nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine. Phenylglycine may substitute for Trp, Tyr, or Phe; citrulline and methionine sulfoxide are neutral nonpolar, cysteic acid is acidic, and ornithine is basic. Proline may be substituted with hydroxyproline and retain the conformation conferring properties of proline.

[0046] As used herein, the term “prevent’' or “preventing” refers to preventing in whole or in part or ameliorating or controlling.

[0047] As used herein, the terms “PEG”, “polyethylene glycol”, or “poly(ethylene glycol)” as used herein refers to any water-soluble poly(ethylene oxide) and includes molecules comprising the structure — (CH2CH2O)n — where n is an integer from 2 to about 800. A commonly used PEG is end-capped PEG, wherein one end of the PEG is capped with a relatively inactive group such as an alkoxy while the other end is a hydroxyl group that may be further modified. An often-used capping group is methoxy and the corresponding endcapped PEG is often denoted mPEG. The notion PEG is often used instead of mPEG. Specific PEG forms of the invention are branched, linear, forked PEGs, and the like and the PEG groups are typically poly disperse, possessing a low polydispersity index of less than about 1.05. The PEG moieties of the invention will, for a given molecular weight, typically consist of a range of ethylene glycol (or ethyleneoxide) monomers. For example, a PEG moiety of molecular weight 2000 Da will typically consist of 43±10 monomers, the average being around 43 monomers. The term “PEGylated” refers to the covalent attachment of PEG to another molecule, such as any of the peptides disclosed herein. Attorney’s Docket No.: 21085.0193P1

[0048] As used herein, the term “fatty acid’' includes saturated fatty’ acids, which do not contain any double or triple bonds in the hydrocarbon chain. Saturated fatty’ acids include, but are not limited to propionic acid (C3) (by way of example, C3 indicates propionic acid has 3 carbon atoms in its hydrocarbon chain; the number of carbon atoms in the hydrocarbon chain of other example fatty’ acids is denoted in analogous fashion herein), butyric acid (C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7). caprylic acid (C8), pelargonic acid (C9). capric acid (CIO), undecylic acid (Cl 1). lauric acid (Cl 2), tridecylic acid (Cl 3), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), margaric acid (C17), stearic acid (Cl 8), isostearic acid (Cl 8), nonadecylic acid (Cl 9), arachidic acid (C20), henei cosy lie acid (C21), behenic acid (C22), tricosy lie acid (C23), lignoceric acid (C24), pentacosylic acid (C25), cerotic acid (C26), heptacosylic acid (C27), montanic acid (C28). nonacocylic acid (C29), melissic acid (C30), henatriacontylic acid (C31), lacceroic acid (C32), psyllic acid (C33), geddic acid (C34), ceroplastic acid (C35) and hexatriacontylic acid (C36).

[0049] As used herein, the term “fatty acid” also includes monounsaturated fatty acids, which contain one double or triple bond in the hydrocarbon chain, and polyunsaturated fatty acids, which contain more than one double and / or triple bond in the hydrocarbon chain. Such acids include, but are not limited to the omega 3, omega 6, omega 9 fatty’ acids, other fatty’ acids such as myristoleic and palmitoleic acid and conjugated fatty acids. Examples of monounsaturated and polyunsaturated fatty acids include but are not limited to, (a) omega 3 fatty acids, such as hexadecatrienoic acid (Cl 6:3); (by way of example. Cl 6:3 indicates hexadecatrienoic acid has 16 carbon atoms in its hydrocarbon chain and 3 double bonds; the number of carbon atoms and double bonds in the hydrocarbon chain of other example unsaturated fatty acids is denoted in analogous fashion herein), alpha linolenic acid (Cl 8: 3) and eicosapentanoic acid (20:5), (b) omega 6 fatty acids, such as linoleic acid (18:2), docosadienoic acid (C22:2), arachidonic acid (C20:4) and tetracosatetraenoic acid (C24:5), (c) omega 9 fatty acids, such as oleic acid (Cl 8: 1), eicosenoic acid (C20: l) and nevronic acid (C24: l), and (d) conjugated fatty’ acids such as rumenic acid (C18:2), eleostatic acid (C 18:3), and rumelenic acid (Cl 8:3).

[0050] The term ’’m-amino-fatty acid” refers to fatty acids which feature an amino group at the distal carbon of the hydrocarbon chain thereof. The co-amino-fatty acid moieties that are used in the context of the present invention can be saturated or unsaturated hydrocarbon chains. These moieties have a carboxylic group at one end of the hydrocarbon chain and an Attorney’s Docket No.: 21085.0193P1 amine group at the other. The hydrocarbon chain connecting the carboxylic and amine groups in such an co-amino-fatty acid moiety typically has from 3 to 32 carbon atoms.

[0051] Exemplary co-amino-fatty acids include, without limitation, 4-amino-butyric acid, 6- amino-caproic acid, 8-amino-caprylic acid, 10-amino-capric acid (10-amino-decanoic acid), 12-amino-lauric acid (12-amino-dodecanoic acid), 14-amino-myristic acid (14-amino- tetradecanoic acid), 14-amino-myristoleic acid, 16-amino-palmitic acid (16-amino- hexadecanoic acid), 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid and 20-amino-arachidonic acid.

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed method and compositions belong. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present method and compositions, the particularly useful methods, devices, and materials are as described. Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. No admission is made that any reference constitutes prior art. The discussion of references states what their authors assert, and applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of publications are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0053] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

[0054] As used herein, ‘"prevent” is meant to mean minimize the chance that a subject who has an increased susceptibility for developing a lipid-mediated inflammatory disease or a lipid disorder will develop lipid-mediated inflammatory disease or a lipid disorder.

[0055] The phrase “lipid disorder” is meant to mean when a subject has an excess of lipids or increased inflammatory lipids in their blood. Lipids include but are not limited to lipids such as ox-LDL (i.e., oxidized PAPC (1 -palmitoyl 2-arachidonyl phophyatidyl choline)). Oxidation of PAPC or PLPC, the lipid components of LDL, produce oxidized lipids. Having Attorney’s Docket No.: 21085.0193P1 a lipid disorder can make one more likely to develop inflammatory disease such as atherosclerosis and heart disease. Lipid disorders can be caused by genetic predispositions or diet.

[0056] The phrase “nucleic acid” as used herein refers to a naturally occurring or synthetic oligonucleotide or polynucleotide, whether DNA or RNA or DNA-RNA hybrid, singlestranded or double-stranded, sense or antisense, which is capable of hybridization to a complementary nucleic acid by Watson-Crick base-pairing. Nucleic acids of the invention can also include nucleotide analogs (e.g., BrdU), and non-phosphodi ester intemucleoside linkages (e.g., peptide nucleic acid (PNA) or thiodiester linkages). In particular, nucleic acids can include, without limitation, DNA, RNA, cDNA, gDNA, ssDNA, dsDNA or any combination thereof.

[0057] COMPOSITIONS

[0058] Disclosed herein are compositions, including pharmaceutical compositions comprising one or more of the peptides described herein. As described herein, the peptides are capable of exerting an anti-inflammatory effect from binding to one or more oxidized lipids (e.g.. 7-ketocholesterol, isolevuglandin), modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4-hydroxynonenal, docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof. In some aspects, the peptides described herein are capable of binding to 5(S)-HPETE, hydroperoxyeicosatetraenoic acid; 12(S)-HPETE. hydroperoxyeicosatetraenoic acid; 15(S)- HPETE, hydroperoxyeicosatetraenoic acid; 13(S)-HPODE, hydroperoxyoctadecadienoic acid; 12(S)-HETE, hydroxy eicosatetraenoic acid; 15(S)-HETE, hydroxyeicosatetraenoic acid; 9(S)-HODE, hydroxy octadecadienoic acid; and 13(S)-HODE, hydroxy octadecadienoic acid. As further described herein, the peptides are capable of enhancing plasma anti-oxidant enzyme PON-1.

[0059] Table 1. Sequences Attorney’s Docket No.: 21085.0193P1

[0060] Disclosed herein are peptides comprising or consisting of a sequence of at least 90% identical to amino acid sequence DFWFAFYDKVI<E1<WI<EAF (SEQ ID NO: 1) or a fragment thereof. In some aspects, the peptide or fragment thereof comprises a W at position 3 and a W at position 14 of SEQ ID NO: 1. In some aspects, the peptide of fragment thereof binds one or more oxidized lipids (e.g., 7-ketocholesterol, isolevuglandin), modified lipids (e.g.. malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4- hydroxynonenal, docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof.

[0061] Disclosed herein are peptides comprising or consisting of a sequence of at least 90% identical to amino acid sequence DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4) or a fragment thereof. In some aspects, the peptide or fragment thereof comprises a W at position 2 and a W at position 4 of SEQ ID NO: 4. In some aspects, the peptide of fragment thereof binds one or more oxidized lipids (e g., 7-ketocholesterol, isolevuglandin), modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4- hydroxynonenal, docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof.

[0062] Disclosed herein are peptides comprising or consisting of a sequence of at least 90% identical to amino acid sequence DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3) or a fragment thereof. In some aspects, the peptide or fragment thereof comprises a W at position 2 and a W at position 14 of SEQ ID NO: 3. In some aspects, the peptide of fragment thereof binds one or more oxidized lipids (e.g., 7-ketocholesterol, isolevuglandin), modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4- hydroxynonenal. docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof. Attorney’s Docket No.: 21085.0193P1

[0063] Disclosed herein are peptides comprising or consisting of a sequence of at least 90% identical to amino acid sequence DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2) or a fragment thereof. In some aspects, the peptide of fragment thereof binds one or more oxidized lipids (e.g., 7-ketocholesterol, isolevuglandin), modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4-hydroxynonenal, docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof.

[0064] Disclosed herein are peptides comprising or consisting of a sequence of at least 90% identical to amino acid sequence DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5) or a fragment thereof. In some aspects, the peptide of fragment thereof binds one or more oxidized lipids (e.g., 7-ketocholesterol, isolevuglandin). modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4-hydroxynonenal, docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof.

[0065] Disclosed herein are peptides comprising or consisting of a sequence of at least 90% identical to amino acid sequence DWLWAFYDKEFEKKKEFF (SEQ ID NO: 6) or a fragment thereof. In some aspects, the peptide of fragment thereof binds one or more oxidized lipids (e.g.. 7-ketocholesterol, isolevuglandin). modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4-hydroxynonenal, docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof.

[0066] In some aspects, the fragment of SEQ ID NO: 1 can be between 4 and 9 amino acids in length. In some aspects, the fragment of SEQ ID NO: 2 can be between 4 and 9 amino acids in length. In some aspects, the fragment of SEQ ID NO: 3 can be between 4 and 9 amino acids in length. In some aspects, the fragment of SEQ ID NO: 4 can be between 4 and 9 amino acids in length. In some aspects, the fragment of SEQ ID NO: 5 can be between 4 and 9 amino acids in length. In some aspects, the fragment of SEQ ID NO: 6 can be between 4 and 9 amino acids in length.

[0067] In some aspects, the N-terminus of any of the peptides or fragments thereof disclosed herein can be acetylated. In some aspects, any of the peptides or fragments disclosed herein can further comprise CHs-tCFhln at the N-terminus. In some aspects, n can be any number between 2 to 14. In some aspects, any of the peptides or fragments disclosed herein can further comprise an amide at the C-terminus.

[0068] In some aspects, any of the peptides or fragments thereof disclosed herein can further comprise a fatty acid moiety, a co-amino fatty acid moiety, or an acetylated co-amino fatty acid moiety’. In some aspects, the peptides or fragments thereof can comprise the acetylated co-amino fatty acid moiety. In some aspects, the acetylated co-amino fatty acid moiety can be Attorney’s Docket No.: 21085.0193P1

[0069] Ac- Aha. In some aspects, the Ac- Aha can be at the N-terminus of the peptide or fragment thereof. In some aspects, the peptides or fragments thereof can comprise the co-amino fatty acid moiety. In some aspects, the co-amino fatty acid moiety can be 4-amino-butanoyl, 6- amino-caproyl, 8-amino-octanoyl, 10-amino-decanoyl, 12-amino-lauroyl, 14-amino- myristoyl, 14-amino-myristoleoyl, 16-amino-palmitoyl, 18-amino-stearoyl, 18-amino-oleoyl, 16-amino-palmitoleoyl, 18-amino-linoleoyl. 18-amino- linol enoyl, or 20-amino- arachidonoyl. In some aspects, the co-amino group can be acetylated. In some aspects, the fatty acid moiety, the co-amino fatty acid moiety, or the acetylated co-amino fatty acid moiety can at the N-terminus of the peptide or fragment thereof.

[0070] Disclosed herein are peptides that can comprise fragments of DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), or DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4). In some aspects, the fragments thereof can comprise a sequence having at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%. 99% identity to SEQ ID NOs: 1. 2, 3, 4. 5, or 6. In some aspects, the fragment or portion retains at least 50%, 75%, 80%, 85%, 90%, 95% or 99% of the biological activity of the reference protein described herein.

[0071] In some aspects, the peptides or fragments thereof disclosed herein can comprise a fatty acid moiety. For example, disclosed herein are peptides comprising or consisting of the sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1 ), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), or DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof, wherein the peptide further comprises a fatty acid. For example, disclosed herein are peptides comprising or consisting of the sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6). or DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4). or a fragment thereof, wherein the peptides further comprises a fatty acid, wherein the peptides can be: butanoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 9); hexanoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 10); octanoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 11); decanoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 12); lauroyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 13); myristoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 14); palmitoyl- Attorney’s Docket No.: 21085.0193P1

[0072] DFWFAFYDKVKEKWKEAF (SEQ ID NO: 15); stearoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 16); palmitoleoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 17); arachidoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 18); behenoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 19); oleoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 20); ricinoleoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 21); linolenoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 22); vacceoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 23); gadoleoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 24); erucoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 25); cetoleoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 26); nervonoyl-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 27); adrenoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 28); a-linolenoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 29); y-linolenoyl- DFWFAFYDKVKEKWKEAF (SEQ ID NO: 30); EPA-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 31); DHA-DFWFAFYDKVKEKWKEAF (SEQ ID NO: 32); butanoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 33); hexanoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 34); octanoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 35); decanoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 36); lauroyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 37); myristoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 38); palmitoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 39); stearoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 40); palmitoleoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 41); arachidoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 42); behenoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 43); oleoyl -DWLKAFYDKVFEKWKEFF (SEQ ID NO: 44); ricinoleoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 45); linolenoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 46); vacceoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 47); gadoleoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 48): erucoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 49); cetoleoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 50); nervonoyl-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 51); adrenoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 52); a-linolenoyl- DWLKAFYDKVFEKWKEFF (SEQ ID NO: 53); y-linolenoyl-

[0073] DWLKAFYDKVFEKWKEFF (SEQ ID NO: 54); EPA-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 55); DHA-DWLKAFYDKVFEKWKEFF (SEQ ID NO: 56); butanoyl- DWLKAFYDKFFEKWKEFF (SEQ ID NO: 57); hexanoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 58); octanoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 59): decanoyl- DWLKAFYDKFFEKWKEFF (SEQ ID NO: 60); lauroyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 61); myristoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 62); palmitoyl- Attorney’s Docket No.: 21085.0193P1

[0074] DWLKAFYDKFFEKWKEFF (SEQ ID NO: 63); stearoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 64); palmitoleoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 65); arachidoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 66); behenoyl- DWLKAFYDKFFEKWKEFF (SEQ ID NO: 67); oleoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 68); ricinoleoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 69); linolenoyl- DWLKAFYDKFFEKWKEFF (SEQ ID NO: 70); vacceoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 71); gadoleoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 72); erucoyl- DWLKAFYDKFFEKWKEFF (SEQ ID NO: 73); cetoleoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 74); nervonoyl-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 75); adrenoyl- DWLKAFYDKFFEKWKEFF (SEQ ID NO: 76); a-linolenoyl- DWLKAFYDKFFEKWKEFF (SEQ ID NO: 77); y-linolenoyl-

[0075] DWLKAFYDKFFEKWKEFF (SEQ ID NO: 78); EPA-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 79); DHA-DWLKAFYDKFFEKWKEFF (SEQ ID NO: 80); butanoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 81); hexanoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 82); octanoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 83); decanoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 84); lauroyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 85); myristoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 86); palmitoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 87); stearoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 88); palmitoleoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 89); arachidoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 90); behenoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 91); oleoyl -DWLWAFYDKVFEKKKEFF (SEQ ID NO: 92); ricinoleoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 93); linolenoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 94); vacceoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 95); gadoleoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 96): erucoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 97); cetoleoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 98); nervonoyl-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 99); adrenoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 100); a-linolenoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 101); y-linolenoyl- DWLWAFYDKVFEKKKEFF (SEQ ID NO: 102); EPA-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 103); DHA-DWLWAFYDKVFEKKKEFF (SEQ ID NO: 104); butanoyl- DWLWAFYDKFFEKKKEFF (SEQ ID NO: 105); hexanoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 106); octanoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 107); decanoyl- DWLWAFYDKFFEKKKEFF (SEQ ID NO: 108); lauroyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 109); myristoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 110); palmitoyl- Attorney’s Docket No.: 21085.0193P1

[0076] DWLWAFYDKFFEKKKEFF (SEQ ID NO: 111); stearoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 112); palmitoleoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 113); arachidoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 114); behenoyl- DWLWAFYDKFFEKKKEFF (SEQ ID NO: 115); oleoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 116); ricinoleoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 117); linolenoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 118); vacceoyl-

[0077] DWLWAFYDKFFEKKKEFF (SEQ ID NO: 119); gadoleoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 120); erucoyl -DWLWAFYDKFFEKKKEFF (SEQ ID NO: 121); cetoleoyl- DWLWAFYDKFFEKKKEFF (SEQ ID NO: 122); nervonoyl-

[0078] DWLWAFYDKFFEKKKEFF (SEQ ID NO: 123); adrenoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 124); a-linolenoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 125); y- linolenoyl-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 126); EPA-

[0079] DWLWAFYDKFFEKKKEFF (SEQ ID NO: 127); DHA-DWLWAFYDKFFEKKKEFF (SEQ ID NO: 128); butanoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 129); hexanoyl- DWFWAFYDKVKEKFKEAF (SEQ ID NO: 130); octanoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 131); decanoy 1-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 132); lauroyl- DWFWAFYDKVKEKFKEAF (SEQ ID NO: 133); myristoyl-

[0080] DWFWAFYDKVKEKFKEAF (SEQ ID NO: 134); palmitoyl-

[0081] DWFWAFYDKVKEKFKEAF (SEQ ID NO: 135); stearoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 136); palmitoleoy 1-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 137); arachidoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 138); behenoyl-

[0082] DWFWAFYDKVKEKFKEAF (SEQ ID NO: 139); oleoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 140); ricinoleoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 141); linolenoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 142); vacceoyl- DWFWAFYDKVKEKFKEAF (SEQ ID NO: 143); gadoleoyl-

[0083] DWFWAFYDKVKEKFKEAF (SEQ ID NO: 144); erucoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 145); cetoleoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 146); nervonoyl-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 147); adrenoyl- DWFWAFYDKVKEKFKEAF (SEQ ID NO: 148); a-linolenoyl-

[0084] DWFWAFYDKVKEKFKEAF (SEQ ID NO: 149); y-linolenoyl-

[0085] DWFWAFYDKVKEKFKEAF (SEQ ID NO: 150); EPA-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 151); or DHA-DWFWAFYDKVKEKFKEAF (SEQ ID NO: 152);

[0086] In the foregoing, the fatty acid moiety is shown at the left side and is linked to the peptide DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF Attorney’s Docket No.: 21085.0193P1

[0087] (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), or DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4). "EP A” indicates a moiety derived from 5,8,11,14,17-eicosapentaenoic acid; and “DHA” indicates a moiety7derived from 4,7,10,13,16,19-docosahexaenoic acid.

[0088] In some instances, the peptide or fragment thereof can be any of the disclosed peptides or fragments thereof comprising an acetylated fatty acid.

[0089] Exemplary fatty acids from which a fatty acid moiety is derived include, without limitation, buty ric acid, caproic acid, caprylic acid, capric acid, decanoic acid, lauric acid, myristic acid, palmitic acid, pentadecanoic acid, stearic acid, arachidic acid, behenic acid, erucic acid, lignoceric acid, margaric acid, myristoleic acid, palmitoleic acid, oleic acid, gadoleic acid, ricinoleic acid, vaccenic acid, linoleic acid, linolenic acid, alpha-linolenic acid, gamma-linolenic acid, licanic acid, margaroleic acid, arachidic acid, gadoleic acid, nervonic acid, arachidonic acid, docosapentaenoic (DPA), eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), and the like.

[0090] In some instances, the peptide can be any of the disclosed peptides comprising a saturated fatty acid. Exemplary saturated fatty7acids include, but are not limited to, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid, henatriacontanoic acid, dotriacontanoic acid, tritriacontanoic acid, tetratri acontanoic acid, pentatriacontanoic acid, and hexatriacontanoic acid.

[0091] In some instances, the peptide can be any of the disclosed peptides comprising an unsaturated fatty acid. Exemplary unsaturated fatty acids include, but are not limited to, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, linoleic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid (EP A), erucic acid, docosahexaenoic acid (DHA). and docosapentaenoic acid.

[0092] The peptides disclosed herein can be modified by either natural processes, such as post-translational processing, or by chemical modification techniques which are well known in the art. Modifications can occur anywhere in the polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. The same type of Attorney’s Docket No.: 21085.0193P1 modification can be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide can have many types of modifications. Modifications include, without limitation, acetylation, acylation, ADP-ribosylation, amidation, covalent cross-linking or cyclization, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of a phosphytidylinositol, disulfide bond formation, demethylation, formation of cysteine or pyroglutamate, formylation, gammacarboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristolyation, oxidation, pegylation. proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, and transfer-RNA mediated addition of amino acids to protein such as arginylation. (See Proteins - Structure and Molecular Properties 2nd Ed., T.E. Creighton, W.H. Freeman and Company, New York (1993); Posttranslational Covalent Modification of Proteins, B.C. Johnson, Ed., Academic Press, New York, pp. 1-12 (1983)).

[0093] Disclosed herein are peptides or polypeptides that can comprise variants of DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4). In some aspects, the variants can comprise a sequence having at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% identity to SEQ ID NOs: 1, 2, 3. 4, 5, or 6. In some aspects, the variants retains at least 50%, 75%, 80%, 85%, 90%, 95% or 99% of the biological activity of the reference protein described herein.

[0094] In some aspects, the peptides or fragments thereof described herein can further comprise 1, 2, 3, 4. 5, 10, 15, 20, 25, 30. 35. 40. 45, 50 amino acid residues at the N-terminal end of the disclosed peptides or fragments thereof. In some aspects, the peptides or fragments thereof described herein can further comprise 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 amino acid residues at the C-terminal end of the disclosed peptides or fragments thereof disclosed herein. In some aspects, the amino acid residues that can be present at either the N-terminal end or the C-terminal end of any of the peptides or fragments thereof disclosed herein can be unimportant for binding one or more oxidized lipids (e.g., 7- ketocholesterol, isolevuglandin), modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4-hydroxynonenal, docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof. Attorney’s Docket No.: 21085.0193P1

[0095] In some aspects, the amino acid residues added to the N-terminal end or the C- terminal end of the peptides or fragments thereof disclosed herein may prevent ubiquitination, improve stability, help maintain the three-dimensional structure of the peptide, or a combination thereof.

[0096] In some aspects, the peptides or fragments thereof disclosed herein can further comprise a peptide or polypeptide having one or more amino acid residues with a modified side chain. In some aspects, one or more amino acids of any of the peptides or fragments thereof disclosed here can have a modified side chain. Examples of side chain modifications include but are not limited to modifications of amino acid groups, such as reductive alkylation; amidination with methylacetimidate: acylation with acetic anhydride; carbamolyation of amino groups with cynate; trinitrobenzylation of amino acid with 2.4.6- trinitrobenzene sulfonic acid (TNBS); alkylation of amino groups with succinic anhydride; and pyridoxylation with pridoxal-5-phosphate followed by reduction with NaBEU.

[0097] In some aspects, the guanidine group of the arginine residue may be modified by the formation of a heterocyclic condensate using a reagent, such as 2, 3-butanedione, phenylglyoxal, and glyoxal. In some aspects, the carboxyl group may be modified by carbodiimide activation via O-acylisourea formation, followed by subsequent derivatization, for example, to a corresponding amide.

[0098] In some aspects, the sulfhydryl group may be modified by methods, such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation with cysteic acid; formation of mixed disulfides by other thiol compounds; a reaction by maleimide, maleic anhydride, or other substituted maleimide; formation of mercury derivatives using 4-chloromercuribenzoate, 4-chloromercuriphenylsulfonic acid, phenylmercury chloride, 2-chloromercuri-4-nitrophenol, and other mercurial agents; and carbamolyation with cyanate at alkaline pH. In addition, the sulfhydryl group of cysteine may be substituted with a selenium equivalent, whereby a diselenium bond may be formed instead of at least one disulfide bonding site in the peptide.

[0099] In some aspects, the tryptophan residue may be modified by, for example, oxidation wi th N-bromosuccinimide or alkylation of the indole ring by 2-hydroxy-5-nitrobenzyl bromide or sulfonyl halide. Meanwhile, the tyrosine residue may be modified by nitration using tetranitromethane to form a 3-nitrotyrosme derivative.

[0100] In some aspects, the modification of the imidazole ring of the histidine residue may be accomplished by alkylation with an iodoacetic acid derivative or N-carbethoxylation with diethylpyrocarbonate. Attorney’s Docket No.: 21085.0193P1

[0101] In some aspects, the proline residue may be modified by, for example, hydroxylation at the 4-position.

[0102] In some aspects, peptides (including any fragments or variants thereof) disclosed herein can further comprise at least one polyethylene glycolated (PEGylated) group attached to the N-terminus. In some aspects, the pegylated peptides have can a longer half-life of the non-pegylated peptides. In some aspects, the pegylated peptides can have a half-life of at least 30 hours. In some aspects, the pegylated peptides can have a half-life of 30. 31. 32. 33. 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 46, 47, 48 hours or longer.

[0103] Polyethylene Glycol (PEG) is a well-known polymer with good solubility in many aqueous and organic solvents, which exhibits low toxicity, lack of immunogenicity, and is clear, colorless, odorless, and stable. For these reasons and others, PEG has been selected as the preferred polymer for attachment, but it has been employed solely for purposes of illustration and not limitation. Similar products may be obtained with other water-soluble polymers, including without limitation; polyvinyl alcohol, other poly (alky lene oxides) such as polypropylene glycol) and the like, poly(oxy ethylated polyols) such as poly(oxy ethylated glycerol) and the like, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl purrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene / maleic anhydride, and polyaminoacids. One skilled in the art will be able to select the desired polymer based on the desired dosage, circulation time, resistance to proteolysis, and other considerations.

[0104] Representative polymeric reagents and methods for conjugating such polymers to an active moiety are described in Harris, J. M. and Zalipsky, S., Eds, Poly(ethylene glycol), Chemistry and Biological Applications, ACS, Washington, 1997; Veronese, F., and J. M. Harris, Eds., Peptide and Protein PEGylation, Advanced Drug Delivery Reviews, 54(4); 453- 609 (2002); Zalipsky, S., et al., "‘Use of Functionalized Poly Ethylene Glycols) for Modification of Polypeptides” in Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenus Press, New York (1992); Zalipsky (1995) Advanced Drug Reviews 16: 157-182; and in Roberts et al., Adv. Drug Delivery7Reviews, 54, 459-476 (2002).

[0105] A wide variety of PEG derivatives are both commercially available and suitable for use in the preparation of the PEG-conjugates of the invention. For example, NOF Corp.'s SUNBRIGHT® Series (peg-drug.com) provides numerous PEG derivatives, including methoxypolyethylene glycols and activated PEG derivatives such as succinimidyl ester, methoxy-PEG amines, maleimides, and carboxylic acids, for coupling by various methods to C-peptide and Nektar Therapeutics' Advanced PEGylation also offers diverse PEG-coupling Attorney’s Docket No.: 21085.0193P1 technologies to improve the safety and efficacy of therapeutics. Additional PEGs for use in forming a C-peptide conjugate of the invention include those available from Polypure (Norway), from QuantaBioDesign LTD (Ohio) and Sunbio, Inc (South Korea). Further PEG reagents suitable for use in forming a conjugate of the invention, and methods of conjugation are described in the Pasut. G., et al., Expert Opin. Then Patents (2004), 14(6) 859-893.

[0106] The PEGylated peptides described herein can have PEG moieties with a molecular weight varying within a range of about 4,000 Da to 80,000 Da. The molecular weight ranges will typically be from about 4000 Da to about 10,000 Da, from about 10,000 Da to about 20,000 Da, from about 20,000 Da to about 30,000 Da, from about 30,000 Da to about 40,000 Da, from about 40,000 Da to about 50,000 Da, from about 50,000 Da to about 60,000 Da, from about 60.000 Da to about 70.000 Da, and from about 70,000 Da to about 80,000 Da. Non-limiting examples of average molecular weights of the PEG moieties are about 10,000 Da, about 20,000 Da, about 30,000 Da, about 40,000 Da, about 50,000 Da, about 60,000 Da, about 70,000 Da, and about 80,000 Da.

[0107] Because virtually all PEG polymers exist as mixtures of diverse high molecular mass, PEG molecular weight (MW) is typically reported as number average (Mn), weight average (Mw), or z-average (Mz) molecular weights. The weight average is probably the most useful of the three, because it fairly accounts for the contributions of different sized chains to the overall behavior of the polymer, and correlates best with most of the physical properties of interest.

[0108] The PEG groups will for a given molecular weight typically consist of a range of ethylene glycol (or ethyleneoxide; OCH2CH2) monomers. For example, a PEG group of molecular weight 2000 Da will typically consist of 43±10 monomers, the average being around 43-44 monomers.

[0109] The PEG groups will typically comprise a number of subunits, e.g., each n, nl or n2 or n3 in any of the claimed compounds may7each independently be from about 1 to about 1000, from about 1 to about 800, from about 1 to about 600, from about 1 to about 400, from about 1 to about 300, from about 1 to about 200. Well-suited PEG groups are such wherein the number of subunits (i.e., nl, n2, and n3) are independently selected from the group consisting of from about 800 to about 1000; from about 800 to about 950; from about 600 to about 850; from about 400 to about 650; from about 200 to about 450, from about 180 to about 350; from about 100 to about 150; from about 35 to about 55; from about 42 to about 62; from about 12 to about 25 subunits, from about 1 to 10 subunits. In some aspects, the PEGylated peptides will have a molecular weight of about 40 kDa, and thus nl and n2 for Attorney’s Docket No.: 21085.0193P1 each PEG chain in the branch chain PEGs will be within the range of about 440 to about 550, or about 450 to about 520.

[0110] Branched versions of the PEG polymer (e.g., a branched 40,000 Da PEG polymer comprised of two or more 10,000 Da to 20,000 Da PEG polymers or the like) having a total molecular weight of any of the foregoing can also be used.

[0111] Representative branched polymers described therein include those having the following generalized structure: (PEG)y-[Core]-[Linker]; where ‘"[Core]’7is a central or core molecule from which extends 2 or more PEG arms, the variable “y” represents the number of PEG arms, and “[Linker]” represents an optional linking moiety (as further defined herein) that ty pically couples the [Core] to the peptide. In some aspects of the branched chain PEGs. at least one polymer arm possesses a terminal functional group suitable (e.g. NHS moiety) for reaction with peptide. Typically, the branched chain polymers of the invention are coupled to the N-terminal amino group of the peptide.

[0112] In some aspects, the linker moiety can represent either a hydrolytically stable, or alternatively, a degradable linker, meaning that the linkage can be hydrolyzed under physiological conditions, e.g.. the linkage comprises an ester, hydrolysable carbamate, carbonate, or other such group. Hydrolytically degradable linkages, useful not only as a degradable linkage within a polymer backbone, but also, in the case of certain embodiments of the invention, for covalently attaching a water-soluble polymer to a peptide, include: carbonate; imine resulting, for example, from reaction of an amine and an aldehyde (see. e.g., Ouchi et al. (1997) Polymer Preprints 38(1 ):582-3); phosphate ester, formed, for example, by reacting an alcohol with a phosphate group; hydrazone, e.g., formed by reaction of a hydrazide and an aldehyde; acetal, e g., formed by reaction of an aldehyde and an alcohol; orthoester, formed, for example, by reaction between a formate and an alcohol; and esters, and certain urethane (carbamate) linkages. Illustrative PEG reagents for use in preparing a releasable peptide conjugate in accordance with the invention are described in U.S. Pat. Nos. 6,348,558, 5,612,460, 5,840,900, 5,880,131, and 6,376,470. Typically, releasable linkers may be attached to any residue in peptide and are not restricted to the N-terminal amino acid.

[0113] Branched PEGs such as those represented generally by the formula. (PEG)y-[Core]- [Linker], above can possess 2 polymer arms to about 8 polymer arms (i.e., “y” ranges from 2 to about 8). Preferably, such branched PEGs typically possess from 2 to about 4 polymer arms. Multi-armed polymers include those having 2, 3, 4, 5, 6, 7 or 8 PEG arms.

[0114] Core molecules in branched PEGs as described herein include polyols, which are then further functionalized. Such polyols include aliphatic polyols having from 1 to 10 carbon Attorney’s Docket No.: 21085.0193P1 atoms and from 1 to 10 hydroxyl groups, including ethylene glycol, alkane diols, alkyd glycols, alkylidene alkyl diols, alkyl cycloalkane diols, 1,5-decalindiol. 4,8- bis(hydroxymethyl)tricyclodecane, cycloalkylidene diols, dihydroxyalkanes, trihydroxyalkanes, and the like. Cycloaliphatic polyols may also be employed, including straight chained or closed-ring sugars and sugar alcohols, such as mannitol, sorbitol, inositol, xylitol, quebrachitol. threitol, arabitol, erythritol, adonitol, ducitol, facose, ribose, arabinose, xylose, lyxose. rhamnose, galactose, glucose, fructose, sorbose, mannose, pyranose, altrose, talose, tagitose, pyranosides, sucrose, lactose, maltose, and the like. Additional aliphatic polyols include derivatives of glyceraldehyde, glucose, ribose, mannose, galactose, and related stereoisomers. Other core polyols that may be used include crown ether, cyclodextrins, dextrins and other carbohydrates such as starches and amylose. Typical polyols include glycerol, pentaerythritol, sorbitol, and trimethylolpropane. Other suitable cores include lysine, and other polyamines, and PEG moieties comprising multiple functional terminal end groups.

[0115] Illustrative multi-armed PEGs having 2 arms, 3 arms, 4 arms, and 8 arms are known in the art, and are available commercially and / or can be prepared following techniques known to those skilled in the art. (See generally Pasut et al., (2004) Protein, peptide and non-peptide drug PEGylation for therapeutic application Expert Opinin. Ther. Patents 14(6) 859-894). Additional branched-PEGs for use in forming a C-peptide conjugate of the present invention include those described in U.S. Patent Application Publication Nos. 20050009988. 20060194940, 20090234070, 20070031371 , U.S. Pat. Nos. 6,664,331 ; 6,362,254; 6,437,025; 6,541,543; 6,664,331; 6,730,334; 6,774,180; 6,838,528; 7,030,278; 7,026,440; 7,053,150; 7,157,546; 7,223,803; 7,265,186; 7,419,600; 7,432,330; 7,432,331; 7,511,094; 7.528,202; 7,589,157; and PCT publication numbers W02005000360, W02005108463. W02005107815, W02005028539 and W0200605108463.

[0116] In some aspects, the peptides or fragments thereof can comprise PEG and a fatty acid. In some aspects, the PEG can be conjugated to the peptide or fragment thereof at the C- terminal end. and the fatty acid can be conjugated to the peptide or fragment thereof at the N- terminal end. In some aspects, the PEG can be conjugated to the peptide or fragment thereof at the N-terminal end, and the fatty acid can be conjugated to the peptide or fragment thereof at the C -terminal end.

[0117] In some aspects, the peptides or fragments thereof described herein can be further modified to improve stability. In some aspects, any of the amino acid residues of the polypeptides or fragments thereof described herein can be modified to improve stability. In Attorney’s Docket No.: 21085.0193P1 some aspects, peptide or polypeptide can have at least one amino acid residue that has an acetyl group, a fluorenylmethoxy carbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, or polyethylene glycol. In some aspects, an acetyl protective group can be bound to the peptide or polypeptide described herein.

[0118] As used herein, the term “stability"’ refers to storage stability (e.g., room-temperature stability) as well as in vivo stability. The foregoing protective group can protect the peptides or fragments thereof described herein from the attack of protein cleavage enzymes in vivo.

[0119] As used herein, the terms “peptide” and “fragments thereof’ can also be used to include functional equivalents of the peptides and the fragments thereof described herein. As used herein, the term “functional equivalents” can refer to amino acid sequence variants having an amino acid substitution, addition, or deletion in some of the amino acid sequence of the peptide or polypeptide while simultaneously having similar or improved biological activity7, compared with the peptide as described herein. In some aspects, the amino acid substitution can be a conservative substitution. Examples of the naturally occurring amino acid conservative substitution include, for example, aliphatic amino acids (Gly, Ala, and Pro), hydrophobic amino acids (He. Leu, and Vai), aromatic amino acids (Phe. Tyr, and Trp), acidic amino acids (Asp and Glu), basic amino acids (His, Lys, Arg, Gin, and Asn), and sulfur-containing amino acids (Cys and Met). In some aspects, the amino acid deletion can be located in a region that is not directly involved in the activity of the peptide disclosed herein.

[0120] In some aspects, the amino acid sequence of the peptides or fragments thereof described herein can include a peptide sequence that has substantial identity7to any of the sequences of the peptides or fragments thereof disclosed herein. As used herein, the term “substantial identity” means that two amino acid sequences, when optimally aligned and then analyzed by an algorithm normally used in the art, such as BLAST, GAP, or BESTFIT, or by visual inspection, share at least about 60%, 70%, 80%, 85%, 90%, or 95% sequence identity. Methods of alignment for sequence comparison are known in the art.

[0121] In some aspects, the amino acid sequence of the peptides or fragments thereof described herein can include a peptide sequence that has some degree of identity or homology to any of sequences of the peptides or fragments thereof disclosed herein. The degree of identity can vary7and be determined by methods known to one of ordinary7skill in the art. The terms “homology"’ and “identity” each refer to sequence similarity between two polypeptide sequences. Homology and identity can each be determined by comparing a position in each sequence which can be aligned for purposes of comparison. When a position Attorney’s Docket No.: 21085.0193P1 in the compared sequence is occupied by the same amino acid residue, then the polypeptides can be referred to as identical at that position; when the equivalent site is occupied by the same amino acid (e.g., identical) or a similar amino acid (e.g., similar in steric and / or electronic nature), then the molecules can be referred to as homologous at that position. A percentage of homology or identity' between sequences is a function of the number of matching or homologous positions shared by the sequences. The peptides described herein can have at least or about 25%, 50%, 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity or homology to the peptide, wherein the peptide is one or more of SEQ ID NOs: 1-6.

[0122] PHARMACEUTICAL COMPOSITIONS

[0123] As disclosed herein, are pharmaceutical compositions, comprising one or more of the peptides or fragments thereof described herein. Also disclosed herein, are pharmaceutical compositions, comprising one or more of the peptides or fragments thereof described herein and a pharmaceutical acceptable carrier. Further disclosed herein are pharmaceutical compositions comprising one or more of the peptides or fragments thereof described herein for reducing the risk, ameliorating one or more symptoms of a lipid-mediated inflammatory disease or enhancing plasma anti-oxidant enzyme PON-1 activity, or treating a lipid disorder.

[0124] In some aspects, the pharmaceutical compositions can comprise: a) a therapeutically effective amount of one or more of the peptides fragments thereof described herein; and b) a pharmaceutically acceptable carrier. For example, described herein are pharmaceutical compositions comprising: a) a therapeutically effective amount of a peptide comprising or consisting of the sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof; and a pharmaceutically acceptable carrier. In some aspects, the peptides described herein can binds one or more oxidized lipids (e.g., 7-ketocholesterol, isolevuglandin), modified lipids (e.g., malondialdehyde, oxidized phosphatidylcholine, or native or oxidized 4- hydroxynonenal. docosahexaenoic acid), lipid hydroperoxides, lipopolysaccharides or a combination thereof.

[0125] In some aspects, the peptide can further comprise an amide at the C-terminus. In some aspects, the N-terminus of the peptide can be acetylated. In some aspects, the peptide can further comprise CHs-(CH2)n at the N-terminus, wherein n is 2 to 14. In some aspects, the Attorney’s Docket No.: 21085.0193P1 peptide can further comprise a fatty acid moiety, a ot-amino fatty acid moiety, or an acetylated co-amino fatty acid moiety

[0126] The pharmaceutical compositions described above can be formulated to include a therapeutically effective amount of one or more of the peptides described herein. Therapeutic administration encompasses prophylactic applications. Based on genetic testing and other prognostic methods, a physician in consultation with their patient can choose a prophylactic administration where the patient has a clinically determined predisposition or increased susceptibility (in some cases, a greatly increased susceptibility) to a lipid-mediated inflammatory disease including but not limited to atherosclerosis, diabetes, Alzheimer's disease, cancer, age-related macular degeneration, arthritis, kidney disease or a combination thereof; or a lipid disorder including but not limited to coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus.

[0127] The pharmaceutical compositions described herein can be administered to the subject (e.g.. a human patient) in an amount sufficient to delay, reduce, or preferably prevent the onset of clinical disease. Accordingly, in some aspects, the patient can be a human patient. In therapeutic applications, compositions can be administered to a subject (e.g., a human patient) already with or diagnosed with coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease. PAD. cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus (or to a subject that is not diagnosed with coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus or to a subject that does not have coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus) in an amount sufficient to at least partially improve a sign or symptom or to inhibit the progression of (and preferably arrest) the symptoms of the condition, its complications, and consequences (e.g., developing a lipid disorder or a lipid-mediated inflammatory disease).

[0128] The compositions and pharmaceutical compositions comprising one or more of the peptides or fragments thereof described herein can be administered to a subject (e.g.. a human patient) already with or diagnosed with a lipid disorder, a lipid-mediated inflammatory Attorney’s Docket No.: 21085.0193P1 disease, or coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease. PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus. In some aspects, the compositions or pharmaceutical compositions can be administered to a subject (e.g., a human patient) already with or diagnosed with lipid disorder, a lipid-mediated inflammatory disease, or coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus or a combination thereof in an amount sufficient to at least partially improve a sign or symptom or to inhibit the progression of (and preferably arrest) the symptoms of the condition, its complications, and consequences. An amount adequate to accomplish this is defined as a "‘therapeutically effective amount.” A therapeutically effective amount of a pharmaceutical composition can be an amount that achieves a cure, but that outcome is only one among several that can be achieved. As noted, a therapeutically effective amount includes amounts that provide a treatment in which the onset or progression of a lipid disorder or a lipid-mediated inflammatory disease or a symptom of a lipid disorder or a lipid-mediated inflammatory disease is ameliorated or is reduced or prevented. One or more of the symptoms can be less severe. In some aspects, recovery can be accelerated in an individual who has been treated with one or more of the compositions or pharmaceutical compositions disclosed herein.

[0129] In some aspects, the pharmaceutical composition can be formulated for intravenous administration. In some aspects, the pharmaceutical composition can be formulated for subcutaneous, intranasal, intramuscular, oral, intravitreal, subretinal, or suprachoroid intravitreal, subretinal, suprachoroid. The compositions or pharmaceutical compositions can be formulated for administration by any of a variety of routes of administration, and can include one or more physiologically acceptable excipients, which can vary depending on the route of administration. As used herein, the term “excipient” means any compound or substance, including those that can also be referred to as “carriers” or “diluents.” Preparing pharmaceutical and physiologically acceptable compositions is considered routine in the art, and thus, one of ordinary skill in the art can consult numerous authorities for guidance if needed.

[0130] The pharmaceutical compositions as disclosed herein can be prepared for oral or parenteral administration. Pharmaceutical compositions prepared for parenteral administration include those prepared for intravenous (or intra-arterial), intramuscular, subcutaneous, intraperitoneal, transmucosal (e.g., intranasal, intravaginal, or rectal), or Attorney’s Docket No.: 21085.0193P1 transdermal (e.g., topical) administration. Intravitreal, subretinal, suprachoroid administration routes can further be used to deliver the peptides disclosed herein. Aerosol inhalation can also be used to deliver the peptide. Thus, compositions can be prepared for parenteral administration or any of the routes of administration described herein that includes the peptides or fragments thereof dissolved or suspended in an acceptable carrier, including but not limited to an aqueous carrier, such as water, buffered water, saline, buffered saline (e.g.. PBS), and the like. One or more of the excipients included can help approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents, and the like. Where the compositions include a solid component (as they may for oral administration), one or more of the excipients can act as a binder or filler (e.g., for the formulation of a tablet, a capsule, and the like). Where the compositions are formulated for application to the skin or to a mucosal surface, one or more of the excipients can be a solvent or emulsifier for the formulation of a cream, an ointment, and the like.

[0131] The pharmaceutical compositions can be sterile and sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation, which is encompassed by the present disclosure, can be combined with a sterile aqueous carrier prior to administration. The pH of the pharmaceutical compositions typically will be between 3 and 11 (e.g., between about 5 and 9) or between 6 and 8 (e.g.. between about 7 and 8). The resulting pharmaceutical compositions in solid form can be packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents, such as in a sealed package of tablets or capsules. The pharmaceutical composition in solid form can also be packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment.

[0132] METHODS OF TREATMENT

[0133] Disclosed herein are methods of enhancing plasma anti-oxidant enzy me PON-1 activity in a subject. In some aspects, the methods can comprise: administering to a subject a therapeutically effective amount of one or more peptides or fragments thereof disclosed herein. In some aspects, the methods can comprise: administering to the subject a therapeutically effective amount of peptide comprising or consisting of a sequence of at least 90% identical to amino acid sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF Attorney’s Docket No.: 21085.0193P1

[0134] (SEQ ID NO: 6), DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof. In some aspects, the methods can further comprise: administering a therapeutically effective amount of one or more peptides or fragments thereof disclosed herein and a pharmaceutically acceptable carrier. In some aspects, the peptide or fragment thereof comprises a W at position 3 and a W at position 14 of SEQ ID NO: 1. In some aspects, the peptide or fragment thereof comprises a W at position 2 and a W at position 4 of SEQ ID NO: 4. In some aspects, the peptide or fragment thereof comprises a W at position 2 and a W at position 14 of SEQ ID NO: 3. In some aspects, the N-terminus of the peptide or fragment thereof can be acety lated. In some aspects, the peptide or fragment thereof can further comprise CH3-(CH2)n at the N- terminus. wherein n can be 2 to 14. In some aspects, the peptide or fragment thereof can further comprise an amide at the C-terminus. In some aspects, the peptide or fragment thereof can further comprise a fatty acid moiety, a co-amino fatty acid moiety, or an acetylated coamino fatty7acid moiety. In some aspects, the peptide of fragment thereof can comprise an acetylated co-amino fatty acid moiety7. In some aspects, the acety lated co-amino fatty7acid moiety can Ac- Aha. In some aspects, the Ac-Aha can b at the N-terminus of the peptide or fragment thereof. In some aspects, the peptide or fragment thereof can comprise the co-amino fatty acid moiety7. In some aspects, the co-amino fatty acid moiety can 4-amino-butanoyl, 6- amino-caproyl, 8-amino-octanoyl, 10-amino-decanoyl, 12-amino-lauroyl, 14-amino- myristoyl, 14-amino-myristoleoyl. 16-amino-palmitoyl. 18-amino-stearoyl, 18-amino-oleoyl, 16-amino-palmitoleoyl, 18-amino-linoleoyl. 18-amino- linolenoyl, or 20-amino- arachidonoyl. In some aspects, the co-amino group can be acetylated. In some aspects, the fatty7acid moiety7, the co-amino fatty7acid moiety7, or the acetylated co-amino fatty7acid moiety7can be at the N-terminus of the peptide or fragment thereof.

[0135] In some aspects, the subject has or has been diagnosed with a lipid-mediated inflammatory7disease. In some aspects, the lipid-mediated inflammatory disease can be atherosclerosis, type 2 diabetes, Alzheimer’s disease, cancer, age-related macular degeneration, arthritis, or kidney disease. In some aspects, the subject has coronary artery7disease, rheumatoid arthritis, diabetes. Alzheimer’s disease. PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus.

[0136] Disclosed herein are methods of treating a subject with a lipid disorder. In some aspects, the methods can comprise: administering to a subject a therapeutically effective amount of one or more peptides or fragments thereof disclosed herein. In some aspects, the methods can comprise: administering to the subject a therapeutically effective amount of Attorney’s Docket No.: 21085.0193P1 peptide comprising or consisting of a sequence of at least 90% identical to amino acid sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), DWFWAFYDKVKEKFKEAF (SEQ ID NO: 4), or a fragment thereof. In some aspects, the methods can further comprise: administering a therapeutically effective amount of one or more peptides or fragments thereof disclosed herein and a pharmaceutically acceptable carrier. In some aspects, the peptide or fragment thereof comprises a W at position 3 and a W at position 14 of SEQ ID NO: 1. In some aspects, the peptide or fragment thereof comprises a W at position 2 and a W at position 4 of SEQ ID NO: 4. In some aspects, the peptide or fragment thereof comprises a W at position 2 and a W at position 14 of SEQ ID NO: 3. In some aspects, the N-terminus of the peptide or fragment thereof can be acetylated. In some aspects, the peptide or fragment thereof can further compriseCH3-(CH2)n at the N- terminus, wherein n can 2 to 14. In some aspects, the peptide or fragment thereof can further comprise an amide at the C-terminus. In some aspects, the peptide or fragment thereof can further comprise a fatty acid moiety, a co-amino fatty acid moiety, or an acetylated oi-amino fatty acid moiety. In some aspects, the peptide of fragment thereof can comprise an acety lated co-amino fatty7acid moiety7. In some aspects, the acety lated co-amino fatty7acid moiety7can Ac- Aha. In some aspects, the Ac-Aha can b at the N-terminus of the peptide or fragment thereof. In some aspects, the peptide or fragment thereof can comprise the co-amino fatty acid moiety. In some aspects, the co-amino fatty acid moiety can 4-amino-butanoyl, 6-amino- caproyl, 8-amino-octanoyl, 10-amino-decanoyl, 12-amino-lauroyl, 14-amino-myristoyl, 14- amino-myristoleoyl, 16-amino-palmitoyl, 18-amino-stearoyl, 18-amino-oleoyl, 16-amino- palmitoleoyl. 18-amino-linoleoyl, 18-amino- linolenoyl, or 20-amino-arachidonoyl. In some aspects, the co-amino group can be acetylated. In some aspects, the fatty7acid moiety, the co- amino fatty7acid moiety, or the acety lated co-amino fatty acid moiety can be at the N-terminus of the peptide or fragment thereof.

[0137] In some aspects, the lipid disorder can be coronary7artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus.

[0138] In some aspects, the subject can be identified as being in need of treatment before the administration step. In some aspects, the subject can have lipid disorder. Examples of lipid disorders include but are not limited to coronary artery disease, rheumatoid arthritis, diabetes, Attorney’s Docket No.: 21085.0193P1

[0139] Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus. In some aspects, the subject can have a lipid-mediated inflammatory disease. Examples of lipid- mediated inflammatory diseases include but are not limited to atherosclerosis, type 2 diabetes, Alzheimer’s disease, cancer, age-related macular degeneration, arthritis or kidney disease.

[0140] In some aspects, any of the peptides or fragments thereof disclosed herein can be delivered or administered to a subject by direct injection into the eye, for example, to treat age-related macular degeneration, for example, by intravitreal, subretinal, or suprachoroid administration.

[0141] Amounts effective for these uses can depend on the severity of the condition, disease or disorder or the severity of the risk of the condition, disease or disorder, and the weight and general state and health of the subject, but generally range from about 0.01 pg to about 1000 pg (e.g., 0.1-100 pg) or 0.1 mg / kg to about 3 mg / kg per body weight per subject of an equivalent amount of the peptide per dose per subject. Suitable regimes for initial administration and booster administrations are typified by an initial administration followed by repeated doses at one or more hourly, daily, weekly, or monthly intervals by a subsequent administration. In some aspects, the peptide can be administered every day. In some aspects, the peptide can be administered once every day. In some aspects, the peptide can be administered every other day. In some aspects, the peptide can be administered once every other day. For example, a subject can receive any of peptides or fragments thereof described herein in the range of about 0.01 to 1,000 pg or 0.1 to 3.0 mg / kg body weight equivalent dose per dose one or more times per week (e.g., 2, 3, 4, 5, 6, or 7 or more times per week). For example, a subject can receive 0.1 to 2,500 pg (e.g.. 2,000, 1,500, 1,000, 500, 100, 10, 1. 0.5, or 0. 1 pg) dose per week. In some aspects, a subject can receive 0.5 to 3.0 mg / kg daily (e.g., 3.5 to 21 mg / kg body weight). In some aspects, a subject can receive 0.5 to 3.0 mg / kg (e.g., 3.5 to 21 mg / kg body weight) daily dose per week. In some aspects, a subject can receive 0.5 to 3.0 mg / kg (e.g., 3.5 to 21 mg / kg body weight) per dose for one or more does per day per week. In some aspects, the peptide can be administered as a dose of 0.50 to 2 mg / kg or any amount in between. In some aspects, the peptide can be administered as a dose of 0.50 to 1 mg / kg or any amount in between. In some aspects, the peptide can be administered as a dose of 0.50 to 0.75 mg / kg or any amount in between. In some aspects, the peptide can be administered as a dose of 0.50, 0.55. 0.60. 0.65. 0.70, 0.75, 0.80 0.85, 0.90. 0.95. 1.0, 1.25, 1.50, 1 .75 to 2 mg / kg or any amount in between. A subject can also receive any of the Attorney’s Docket No.: 21085.0193P1 peptides or fragments thereof described herein in the range of 0. 1 to 3,000 pg per dose once every two or three weeks. In some aspects, a subject can also receive any of the peptides or fragments thereof described herein in the range of 0.5 to 3.0 mg / kg body weight per dose once every two or three weeks. A subject can also receive 2 mg / kg every week (with the weight calculated based on the weight of the peptide or polypeptide described herein and the weight in kg calculated based on the weight of the subject).

[0142] The total effective amount of peptide in the pharmaceutical compositions disclosed herein can be administered to a mammal as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol in which multiple doses are administered over a more prolonged period of time (e.g., a dose every 4-6. 8-12. 14-16, or 18-24 hours, or every 2-4 days, every other day, 1-2 weeks, or once a month). Alternatively, continuous intravenous infusions sufficient to maintain therapeutically effective concentrations in the blood are also within the scope of the present disclosure.

[0143] The therapeutically effective amount of one or more of the peptides or fragments thereof present within the compositions described herein and used in the methods as disclosed herein applied to mammals (e.g., humans) can be determined by one of ordinary skill in the art with consideration of individual differences in age, weight, and other general conditions (as mentioned above).

[0144] EXAMPLES

[0145] Example 1 : Apolipoprotein A-I mimetic peptides with higher potency

[0146] Apolipoprotein A-I mimetic peptide 4F (Ac-DWFKAFYDKVAEKFKEAF-NFE;

[0147] SEQ ID NO: 157) has been shown to exhibit properties similar to the major protein component of high-density lipoproteins (HDL), the apolipoprotein A-I (apoA-I). In several situations, peptide 4F has been shown to be superior to apoA-I. Peptide 4F has been shown to be anti-inflammatory and ameliorate lipid-mediated inflammatory diseases such atherosclerosis, diabetes, Alzheimer’s disease, several ty pes of cancer, age relate macular degeneration (AMD), arthritis, and kidney disease. In addition, the efficacy of the peptide 4F has been shown in both preclinical and clinical studies.

[0148] Disclosed herein are peptides demonstrating a marked improvement in the efficacy compared to 4F which can reduce the cost of production and decrease the dosage.

[0149] The apoA-I mimetic peptide 4F has the sequence AC-DWFKAFYDKVAEKFKEAF-NH2 (SEQ ID NO: 157). The interfacial Trp residue has been shown to be important for several anti-inflammatory properties of the peptide 4F, Attorney’s Docket No.: 21085.0193P1 including removal of oxidized lipids from oxidized LDL. Considering the importance of the nonpolar face aromatic residues, two analogs of the peptide 4F were synthesized with two Trp residues. SEQ ID NO: 1 shows that Trp is at the center of the nonpolar face, and in SEQ ID NO: 4, Trp is at the polar-nonpolar interface. The sequence and helical wheel representations of these peptides along with that of the peptide 4F are shown in FIG. 1.

[0150] The peptides were synthesized using the solid phase peptide synthesis method. To study the anti-inflammatory properties of these peptides, 5pL of peptide solutions (Img / ml) were incubated either 50pl of plasma from apoE null mice or LDL-receptor null mice and the peptide-mediated decrease in lipid hydroperoxides was determined using DCF A method. The results are shown in FIG. 2. These results showed that the peptide with two Trp amino acids (SEQ ID NO: 1) at the center is more than two times more effective that either the original 4F (SEQ ID NO: 7) or the peptide with two Trp amino acids (SEQ ID NO: 4) at the polar- nonpolar interface.

[0151] To support these observations, peptides were studied for their ability7to enhance paroxonase 1 (PON-1). It is known that increased amount of lipid hydroperoxides in plasma decreases the plasma anti-oxidant enzyme PON-1, the enzyme responsible for converting oxidized lipids and LDL into nonoxidized and anti-inflammatory LDL. Five pl of peptide solutions (of concentration Img / ml) were added to 5 g of PON- 1 in 200 pl of plasma from either apoE null mice or LDL-receptor null mice. Paraoxan (Sigma cat# D-9286 chem name: Diethyl p-nitrophenyl phosphate, IpL) was used as the substrate. One unit of PON is defined as Inmol of 4-nitrophenol formed per minute under the above conditions. Enzy matic activity7is calculated from the molar extinction coefficient 17100 Macin'1. Units of enzyme activity7per = pAbs per minute (nmole of 4-nitrophenol formed) volume of plasma used. Results are shown in FIG. 3. These results show that the peptide with two Trp residues at the center (2Wc4F; SEQ ID NO: 1) enhanced the PON-1 activity more than two times compared to control and peptide 4F.

[0152] The results show that the peptide w ith the sequence Ac-DFWFAFYDKVKEKWKEAF-NH2(SEQ ID NO: 1) is the most effective peptide compared to SEQ ID NO: 4. In some aspects, the replacement of Ac- group with CH3-(CH2)n where n= 2 to 14 enhances the activity7of this peptide.

[0153] Further, peptide analogs of the apoA-I mimetic peptides 5F and 6F with two Trp residues at the center of the non-polar face w ould also be effective. The peptide sequence of apoA-I mimetic peptide 5F comprises the sequence DWLKAFYDKVFEKFKEFF (SEQ ID NO: 153) whereas the peptide sequence of apoA-I mimetic peptide 6F comprises the Attorney’s Docket No.: 21085.0193P1 sequence DWLKAFYDKFFEKFKEFF (SEQ ID NO: 154). The peptide analogs of the apoA- I mimetic peptides 5F and 6F, namely DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2 - c modified 5F), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3 - c modified 6F), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5 - i modified 5F), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6 - i modified 6F), can also can be highly potent peptide drug candidates for the amelioration of lipid-mediated inflammatory diseases such atherosclerosis, diabetes. Alzheimer’s disease, several types of cancer, age related macular degeneration (AMD), arthritis, kidney diseases.

Claims

Atorney’s Docket No.: 21085.0193P1CLAIMSWHAT IS CLAIMED IS:

1. A peptide comprising or consisting of a sequence of at least 90% identical to amino acid sequence DFWFAFYDKVKEKWKEAF (SEQ ID NO: 1), DWLKAFYDKVFEKWKEFF (SEQ ID NO: 2), DWLKAFYDKFFEKWKEFF (SEQ ID NO: 3), DWLWAFYDKVFEKKKEFF (SEQ ID NO: 5), DWLWAFYDKFFEKKKEFF (SEQ ID NO: 6), DWFWAFYDI<VKEI<FI<EAF (SEQ ID NO: 4), or a fragment thereof.

2. The peptide of claim 1, wherein the peptide or fragment thereof comprises a W at position 3 and a W at position 14 of SEQ ID NO: 1.

3. The peptide of claim 1, wherein the peptide or fragment thereof comprises a W at position 2 and a W at position 4 of SEQ ID NO: 4.

4. The peptide of claim 1 , wherein the peptide or fragment thereof comprises a W at position 2 and a W at position 14 of SEQ ID NO: 3.

5. The peptide of any of the preceding claims, wherein the peptide or fragment thereof binds one or more oxidized lipids, lipid hydroperoxides, or lipopolysaccharides.

6. The peptide of any of the preceding claims, wherein the N-terminus is acetylated.

7. The peptide of any of the preceding claims, further comprising CH?-(CH2)n at the N- terminus, wherein n is 2 to 14.

8. The peptide of any of the preceding claims, further comprising an amide at the C- terminus.

9. The peptide of any of the preceding claims, wherein the peptide enhances plasma antioxidant enzyme PON-1.Attorney’s Docket No.: 21085.0193P110. The peptide of any of the preceding claims, further comprising a faty acid moiety, a co-amino fatty acid moiety, or an acetylated co-amino fatty acid moiety.

11. The peptide of claim 10, wherein the peptide comprises the acetylated co-amino fatty acid moiety.

12. The peptide of claim 11, wherein the acetylated co-amino fatty acid moiety is Ac-Aha.

13. The peptide of claim 12, wherein the Ac-Aha is at the N-terminus of the peptide.

14. The peptide of claim 10, wherein the peptide comprises the co-amino fatty acid moiety.

15. The peptide of claim 14, wherein the co-amino fatty acid moiety is 4-amino-butanoyl, 6-amino-caproyl. 8-amino-octanoyL 10-amino-decanoyl, 12-amino-lauroyl, 14- amino-myristoyl, 14-amino-myristoleoyl, 16-amino-palmitoyl, 18-amino-stearoyl, 18- amino-oleoyl, 16-amino-palmitoleoyl, 18-amino-linoleoyl, 18-amino- linolenoyl, or 20-amino-arachidonoyl.

16. The peptide of claim 15, wherein the co-amino group is acetylated.

17. The peptide of claim 10, wherein the fatty acid moiety, the co-amino fatty acid moiety, or the acetylated co-amino fatty acid moiety is at the N-terminus of the peptide.

18. A pharmaceutical composition comprising the peptide of any of the preceding claims.

19. A pharmaceutical composition for reducing the risk or ameliorating one or more symptoms of a lipid-mediated inflammatory disease, the pharmaceutical composition comprising: a) a therapeutically effective amount of any of the peptides of any of the preceding claims; and b) a pharmaceutically acceptable carrier.Attorney’s Docket No.: 21085.0193P120. The pharmaceutical composition of claim 19, wherein the lipid-mediated inflammatory disease is atherosclerosis, diabetes, Alzheimer’s disease, cancer, age- related macular degeneration, arthritis or kidney disease.

21. A method of enhancing plasma anti-oxidant enzy me PON-1 activity' in a subject, the method comprising: administering to a subject a therapeutically effective amount of any of the peptides of any of claims 1-17; and a pharmaceutically acceptable carrier.

22. The method of claim 21, wherein the subject is identified as being in need of treatment before the administration step.

23. The method of claim 22, wherein the peptide is formulated for intravenous, subcutaneous, intranasal, intravitreal, subretinal, suprachoroid, or oral administration.

24. The method of claims 22-23. wherein the subject has or has been diagnosed with a lipid-mediated inflammatory disease.

25. The method of claim 24, wherein the lipid-mediated inflammatory disease is atherosclerosis, type 2 diabetes, Alzheimer’s disease, cancer, age-related macular degeneration, arthritis or kidney disease.

26. The method of claim 21, wherein the subject has coronary' artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, PAD, cerebral vascular disease, diabetes- derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus.

27. The method of claims 21-26, wherein the peptide is administered as a composition comprising the peptide and a pharmaceutically acceptable carrier.

28. The method of claim 27, wherein the peptide is administered in an amount of about 0.01 mg / kg to about 12 mg / kg.Attorney’s Docket No.: 21085.0193P129. A method for treating a subject with a lipid disorder, the method comprising administering to the subject an effective amount of any one of the peptides of claims 1-17, or a composition thereof.

30. The method of claim 29, wherein the peptide is administered as a composition comprising the peptide and a pharmaceutically acceptable carrier.

31. The method of claim 29, wherein the lipid disorder is coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, age-related macular degeneration, congestive heart failure, and / or systemic lupus.

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