# US 2013/0156723 A1 · Synthetic stereoisomer peptides in the retro-inverso and inverso configuration, and with cyclic and linear structure, their polymer conjugates, their encapsulation in polymer particles, and uses thereof

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- Number: US 2013/0156723 A1
- Document ID: US20130156723A1
- Status: Published application
- Kind: A1
- Application number: 13/732,951
- Filed: 2013-01-02
- Published: 2013-06-20
- Earliest claimed: 2009-10-29
- Inventors: LUCIA IRENE GONZALEZ
- Web page: https://patentgrep.com/patent/US20130156723A1

## CPC

- C08G 63/912: {derived from hydroxycarboxylic acids}
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- C07K 7/06: having 5 to 11 amino acids
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 7/64: Cyclic peptides containing only normal peptide links
- C07K 17/08: the carrier being a synthetic polymer
- C08F 222/38: Amides
- C12N 9/96: Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
- 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)
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- 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)
- 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)
- C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

This invention discloses ligand-targeted multi-stereoisomer peptide-polymer conjugate compounds comprising a plurality of different synthetic and chemically modified stereoisomer peptides that have been conjugated to a biocompatible polymer carrying a peptide ligand for targeted delivery or encapsulated in ligand targeted polymer nanoparticles. The unique physicochemical properties of the stereoisomer peptides provide therapeutic compounds with ideal biopharmaceutical properties. The stereoisomer peptides carried by the polymer are delivered to cells or tissues to inhibit, suppress, block, or disrupt, simultaneously and independently, the functional domain of a different disease causing protein. Therefore the compounds are useful therapeutics for the treatment of abnormal angiogenesis and inflammation which are the hall mark of most human diseases including but not limited to cancer, metastasis, pathological conditions of the eye, cardiovascular, brain, and neurodegenerative disorders, diabetes, and diseases caused by infectious microorganisms.

## Claims

### Claim at position 1

1-17. (canceled)

### Claim 18

A therapeutic ligand-targeted multi-stereoisomer peptide-polymer conjugate compound represented by the formula: [sP]n-(L)-Pol-PL
wherein:
sP is a plurality of different stereoisomer peptides D-amino acids, D- and unnatural amino acids, and D- L-, and unnatural amino acids in the retro-inverso or inverso configuration, and said configuration is cyclic or linear alpha-helix or linear beta-sheet, wherein:
said a plurality of different stereoisomer peptides are independently selected from the group consisting of SEQ ID NOs 1-98 disclosed in SEQ_Listing_LIGonzalez_ST25.
said a plurality of different stereoisomer peptides inhibit, antagonize, bind, block, disrupt, interact and suppress, each simultaneously and independently, and positively, or negatively the functional domain of a specific protein.
said a plurality of different stereoisomer peptides simultaneously and independently target a protein, wherein:
the target protein is a growth factor, a receptor, an integrin, a protein kinase, a heat shock protein, a neuroprotein, a hormone, a signaling protein, a chemokine, a membrane protein, and endothelial protein, and a matrix protein, wherein:
the proteins are VEGF, EGFR, VEGFR, PDGFR, IGF-1, HSP90, HSP70, HSP72, HSC70; p13K, TAK-1, GSK3, mTOR, NgR, CCL5, CCR3, CXCR6, avβ3, avβ5, a5β1, p53, neuroepithelin, proepithelin, Collagen IV, tumnstatin, Collagen XVIII, somatostatin, endostatin, angiostatin, thrombospondin, BDAI, HIV gp120, gp41, p24, tat, protease, integrase, reverse transcriptase, Vif, PRNP, PfCDPK1, UIS3, DHFR-TS, Mersacidin, Pep5, Epicidin peptide-2, LEAP-2, Acps, pantothenate synthetase, Cystatin C, and defensin.
said unnatural amino acids are selected from the group consisting of Sar, Nle, Nvl, NMe-Val, NMe-Leu, NMe-Nle, Cpg, Chg, Hyp, Oic, Igl, Aib, Aic, Pip, BhTic, BhPro, Tiq, Nip, Thz, Thi, 4GuaPr, 4Pip, Idc, Bip, me-Tyr, I-Tyr, Igl, BhTic, BhPhe, AMeF, BPhe, Phg, Anc, Atc, NMe-Phe, NMe-Lys N, hPhe, BhTrp, pI-Phe, Aic, NMe-Lys Orn, Dpr 2, Dbu, N-eMe-K, N-eEt-K, N-eIPr-K, bhomoK, Acm, Ahx, K(NPeg11), K(NPeg27), Cit, hArg, hCit, and NMe-Arg.
said cyclic structure has an amide bond created by head-to-tail linking of the terminal residues of said stereoisomer peptide; a lactam bond created by linking the side chains of core or terminal residues of said stereoisomer peptide; a disulfide bond created by linking two terminal Cys residues or core Cys residues of said stereoisomer peptide; or a thioether bond created by linking a Cys side chain and the side chain of serine or threonine of said stereoisomer peptide.
said linear alpha-helix is stabilized by cyclization of the terminal amino acid residues of said stereoisomer peptide, or by linking the terminal amino acid residues of said stereoisomer peptide to each end of ethylene-glycol based linker.
n is an integer from 2 to 100, inclusive, stereoisomer peptides, independently selected from the group consisting of SEQ ID NOs 1-98 disclosed in SEQ_Listing_LIGonzalez_ST25.
L is a linker comprising 2 to 5 amino acid residues, wherein:
the amino acids are independently selected from the group consisting of D-Lys, D-Gly, D-Phe, D-Leu, D-Ser D-Tyr, D-Glu, D-Gln, and D-Asn
said linker is conjugated by covalent bond to an activated carboxyl group of a polymer branch
said linker is cleavable and non-cleavable, wherein:
cleavable linker is bound to a stereoisomer peptide inhibitor or antagonist
non-cleavable linker is bound to a stereoisomer peptide ligand, PL
Pol is a biocompatible polymer, wherein:
said polymer is poly lactic-co-glycolic acid (PLGA), polylactic acid (PLA), Poly ε-caprolactone (PCL), N-(2-Hydroxypropyl) methacrylamide (HPMA), polyethylene glycol (PEG), or pluronic polymeric micelles (PPM).
PL is a peptide ligand, wherein,
said peptide ligand is a cell penetrating peptide, a receptor affinity peptide, a transport peptide, a transduction domain peptide, a chemotactic peptide or a permeation peptide.

### Claim 19 (depends on 1)

The therapeutic compound of claim 1, wherein said unnatural amino acid is Sar, Nle, NMe-Val, or NMe-Leu

### Claim 20 (depends on 1)

The compound of claim 1, wherein said cyclic structure has an amide bond, a disulfide bond, or a lactam bond.

### Claim 21 (depends on 1)

The therapeutic compound of claim 1, wherein said linear alpha-helix is stabilized by terminal amino acid residues linkage.

### Claim 22 (depends on 1)

The therapeutic compound of claim 1, wherein said linker is conjugated by covalent bond to an activated carboxyl group of a single polymer branch, and wherein said polymer branch carries a single stereoisomer peptide conjugated to said linker

### Claim 23 (depends on 1)

The therapeutic compound of claim 1, wherein said branched polymer carries a plurality of different stereoisomer peptides conjugated each with said linker bound to a single polymer branch of said branched polymer.

### Claim 24 (depends on 1)

The therapeutic compound of claim 1, wherein said biocompatible polymer is a polymer chain, a branched polymer, and polymer nanoparticles.

### Claim 25 (depends on 24)

The therapeutic compound of claim 24, wherein said polymer nanoparticles are loaded by encapsulation with a plurality of different stereoisomer peptides conjugated each separately to a polymer chain.

### Claim 26 (depends on 25)

The therapeutic compound of claim 25, wherein said polymer nanoparticles have a conjugated peptide ligand, wherein the peptide ligand is a receptor affinity peptide, a cell penetrating peptide, or a transport peptide.

### Claim 27 (depends on 1)

The therapeutic compound of claim 1, wherein said a plurality of different stereoisomer peptides have the SEQ ID NO 7: Cys Gln Glu Tyr Pro Asp Cys; SEQ ID NO 8: Cys Gly Asn Gly Arg Gly Cys; SERQ ID NO 10: Cys Arg Arg Arg Arg Arg Arg Arg Arg Cys; SEQ ID NO 11: Cys Tyr Ser Asn Ser Gly Cys; SEQ ID NO 12: Gly Asn Lys Arg Thr Arg Gly; SEQ ID NO 17: Cys Ala Thr Trp Leu Pro Pro Arg Cys; SEQ ID NO 20: Pro Gln Pro Arg Pro Leu; SEQ ID NO 26: Cys Ser Leu Tyr Tyr Ile Gln Gln Asp Thr Lys Cys; SEQ ID NO 27: Cys Trp Cys Phe Trp Lys Thr Cys Thr Cys, and SEQ ID NO 72: Lys Arg Leu Lys Glu Lys His Cys, wherein the sequences are synthetic, and chemically modified.

### Claim 28 (depends on 1)

The therapeutic compound of claim 1, wherein said a plurality of different stereoisomer peptides inhibit, bind or antagonize each and specifically the functional domain of a different protein.

### Claim 29 (depends on 1)

The therapeutic compound of claim 1, wherein the target protein is VEGF, VEGFR, p13K, GSK3, avβ3, avβ5, p53, proepithelin, Collagen, tumnstatin, gp160, wherein the different proteins are targeted independently by the plurality of different stereoisomer peptides.

### Claim 30 (depends on 1)

The therapeutic compound of claim 1, wherein said peptide-ligand targets a tissue or cell in the body of a mammal.

### Claim 31 (depends on 30)

The therapeutic compound of claim 30, wherein said tissue is a tumor or a proliferative angiogenic blood vessel, wherein said cell is a cancer cell, a white blood cell, a nerve cell, a dendritic cell, or a brain cell.

### Claim 32 (depends on 30)

The therapeutic compound of claim 30, is used to treat said mammal, wherein the mammal is human or animal

### Claim 33 (depends on 32)

The therapeutic compound of claim 32, is administered in an effective amount to said human suffering from abnormal angiogenesis.

### Claim 34 (depends on 33)

The therapeutic compound of claim 33, wherein said abnormal angiogenesis is cancer, metastasis, inflammation, macular degeneration, choroidal neovascularization, diabetic retinopathy, rheumatoid arthritis, diabetes, cardiovascular disease, brain disease, neurological disease, Alzheimer's disease.

### Claim 35 (depends on 34)

The therapeutic compound of claim 34, wherein a pathogen is involved in said cancer and inflammation, wherein said pathogen is virus or bacteria.

### Claim 36 (depends on 33)

The therapeutic compound of claim 33, wherein said effective amount of the compound is administered by the oral, parenteral, topical, pulmonary, mucosal, or transdermal route.