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

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.

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.