# US 2014/0194369 A1 · Cyclic lactadherin peptide mimetics and their uses

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- Number: US 2014/0194369 A1
- Document ID: US20140194369A1
- Status: Published application
- Kind: A1
- Application number: 14/125,906
- Filed: 2012-05-24
- Published: 2014-07-10
- Earliest claimed: 2011-06-13
- Assignees: The Trustees of Boston College
- Applicants: Trustees of Boston College
- Inventors: Jianmin Gao; Hong Zheng
- Web page: https://patentgrep.com/patent/US20140194369A1

## CPC

- C07K 7/64: Cyclic peptides containing only normal peptide links
- A61K 49/0043: {Fluorescein, used in vivo}
- A61K 49/0056: {Peptides, proteins, polyamino acids}
- A61K 49/085: {conjugated systems}
- A61K 49/14: Peptides, e.g. proteins
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- G01N 33/92: involving lipids, e.g. cholesterol {, lipoproteins, or their receptors (steroid hormones G01N33/743)}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- G01N 2510/00: Detection of programmed cell death, i.e. apoptosis
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Provided herein is a new class of cyclic lactadherin peptides (cLac) that mimic the natural phosphatidylserine (PS)-binding activity of the parent lactadherin protein. These cLacs are useful as small molecule indicators of early stage of apoptosis and of treatment efficacy evaluation.

## Claims

### Claim 1

A cyclic peptide comprising at least 10 but no more than 20 amino acid residues having the formula I:
wherein A1 and A2 are hydrophobic amino acid residues that are appropriate for lipid membrane binding, wherein the side chains of these hydrophobic amino acid have an added cLogP value of between 5 and 9, and wherein the hydrophobic amino acid residues are in the D or L configuration, are natural or unnatural, and hydrophobic amino acid are substituted or unsubstituted;
wherein A4 is an amino acid with polar side chain that can form strong hydrogen bonding or salt bridge;
wherein A5 is a small hydrophobic amino acid;
wherein A6 is an amino acid with polar side chain that can form strong hydrogen bonding;
wherein A3, A7 and A9 are neutral amino acid residues, wherein n=1-3, x=1-5 and y=2-6, and when there are multiples of A3, A7 and A9, they can be the same amino acid residues or different amino acid residues;
wherein A8 is a positively charged amino acid; and
wherein A10 is an amino acid with a negatively charged side chain.

### Claim at position 2

2-25. (canceled)

### Claim 26 (depends on 1)

The cyclic peptide of claim 1, wherein the substituent is a halogenated aromatic or aliphatic amino acid, a halogenated aliphatic or aromatic modification on the hydrophobic side chain, or an aliphatic or aromatic modification.

### Claim 27 (depends on 26)

The cyclic peptide of claim 26, wherein the aliphatic modification is between 1 to 10 carbons, and wherein the aliphatic modification is straight chain alkyl or alkenyl.

### Claim 28 (depends on 1)

The cyclic peptide of claim 1, wherein A1 and A2 are each individually selected from the group consisting of alanine, glycine, histidine, proline, serine, threonine, tyrosine, cysteine, methionine, valine, tryptophan, phenylalanine, leucine, isoleucine, biphenylalanine, methyl-phenylalanine, terphenylalnine, p-phenyl-L-phenylalanine, 3-(2-naphthyl)-L-alanine, 3-(1-naphthyl)-L-alanine, 4-Iodo-L-phenylalanine, 4-tert-bultyl-L-phenylalanine, 4-Bromo-L-phenylalanine, 3,4,5-Trifluoro-L-phenylalanine, and pentafluoro-L-phenylalanine.

### Claim 29 (depends on 1)

The cyclic peptide of claim 1, wherein A4 is selected from the group consisting of histidine, asparagine, glutamine, lysine, arginine and its analogues and derivatives.

### Claim 30 (depends on 1)

The cyclic peptide of claim 1, wherein A5 is selected from the group consisting of isoleucine, alanine, valine, leucine and methionine.

### Claim 31 (depends on 1)

The cyclic peptide of claim 1, wherein A6 is selected from the group consisting of glutamine, tyrosine, serine, asparagine, histidine, cysteine and threonine.

### Claim 32 (depends on 1)

The cyclic peptide of claim 1, wherein A3, A7 and A9 are each individually selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, cysteine, tyrosine, tryptophan, serine, threonine, proline, methionine, phenylalanine, glutamine, asparagine and propargyl glycine (ppG).

### Claim 33 (depends on 1)

The cyclic peptide of claim 1, wherein A3, A7 and A9 are each individually alanine or glycine.

### Claim 34 (depends on 1)

The cyclic peptide of claim 1, wherein A8 is selected from the group consisting of lysine, arginine and the analogues and derivatives of these amino acids.

### Claim 35 (depends on 1)

The cyclic peptide of claim 1, wherein A10 is selected from the group consisting of aspartic acid, glutamic acid and the analogues and derivatives of these amino acids.

### Claim 36 (depends on 1)

The cyclic peptide of claim 1, wherein the cyclic peptide binds to phosphatidylserine.

### Claim 37 (depends on 1)

The cyclic peptide of claim 1, wherein the cyclic peptide is selected from the group consisting of WBipGHIQGGRGGGD (SEQ ID NO: 1), WBipGHIQAGRGGGD (SEQ ID NO: 2), WBipGHIQGARGGGD (SEQ ID NO: 3), cLac-A5 or WBipGHIQGGRGGAD (SEQ ID NO: 4), WBipGHIQGGRGGGGD (SEQ ID NO: 5), WBipGHIQGGRGGGGGD (SEQ ID NO: 6), WBipGHppGQGGRGGGD (SEQ ID NO: 7), WBipGHIQGppGRGGGD (SEQ ID NO: 8), WBipGHIQGRGGGD (SEQ ID NO: 9), WBipGHIQGGGRGGGD (SEQ ID NO: 10), WBipGHIQGppGRGGAD (SEQ ID NO: 11), D-WBipGHIQGGRGGGD (SEQ ID NO: 12) or a peptide variant thereof.

### Claim 38 (depends on 1)

The cyclic peptide of claim 1, further comprising a label.

### Claim 39 (depends on 1)

A composition comprising a cyclic peptide of claim 1 and a pharmaceutically acceptable carrier.

### Claim 40 (depends on 1)

A kit comprising a cyclic peptide of claim 1 and instructions for using the cyclic peptide or composition to detect phosphatidylserine exposure or apoptosis in a sample.

### Claim 41 (depends on 1)

A method of detecting phosphatidylserine exposure on a cell, comprising contacting a biological sample with the cyclic peptide of claim 1 and measuring the cyclic peptide attached to the biological sample, wherein the amount of cyclic peptide attached is above a reference level indicates the presence of phosphatidylserine exposure on a cell in the biological sample.

### Claim 42 (depends on 1)

A method of detecting apoptosis of a cell, comprising contacting a biological sample with the cyclic peptide of claim 1 and measuring the cyclic peptide attached to the biological sample, wherein the amount of cyclic peptide attached is above a reference level indicates the presence of apoptosis in the biological sample.

### Claim 43 (depends on 1)

A method of detecting apoptosis in a tissue in a subject in need thereof, contacting the tissue with the cyclic peptide of claim 1 and measuring the cyclic peptide attached to the tissue, wherein the amount of cyclic peptide attached is above a reference level indicates the presence of apoptosis in the tissue.

### Claim 44 (depends on 39)

A kit comprising a composition of claim 39 and instructions for using the cyclic peptide or composition to detect phosphatidylserine exposure or apoptosis in a sample.

### Claim 45 (depends on 39)

A method of detecting phosphatidylserine exposure on a cell, comprising contacting a biological sample with a composition of claim 39 and measuring the cyclic peptide attached to the biological sample, wherein the amount of cyclic peptide attached is above a reference level indicates the presence of phosphatidylserine exposure on a cell in the biological sample.

### Claim 46 (depends on 39)

A method of detecting apoptosis of a cell, comprising contacting a biological sample with a composition of claim 39 and measuring the cyclic peptide attached to the biological sample, wherein the amount of cyclic peptide attached is above a reference level indicates the presence of apoptosis in the biological sample.

### Claim 47 (depends on 39)

A method of detecting apoptosis in a tissue in a subject in need thereof, contacting the tissue with or a composition of claim 39 and measuring the cyclic peptide attached to the tissue, wherein the amount of cyclic peptide attached is above a reference level indicates the presence of apoptosis in the tissue.