PEPTIDE CONJUGATES
Methods and compositions related to the selective, specific disruption of multiple ligand-receptor signaling interactions, such as ligand-receptor interactions implicated in disease, are disclosed. These interactions may involve multiple cytokines in a single receptor family or multiple ligand receptor interactions from at least two distinct ligand-receptor families. The compositions may comprise polypeptides having composite sequences that comprise sequence fragments of two or more ligand binding sites. The methods and compositions may involve sequence fragments of two or more ligand binding sites that are arranged to conserve the secondary structure of each of the ligands from which the sequence fragments were taken.
1 . A method of treating a γc-cytokine-mediated disease, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising:
a nucleotide sequence encoding a therapeutic composite peptide; and
a pharmaceutical acceptable carrier, diluent, excipient or combination thereof.
2 . The method claim 1 , wherein the therapeutic composite peptide inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor, and wherein the therapeutic composite peptide comprises a region 1-20 amino acids in length that aligns with a corresponding region of a single target ligand or receptor.
3 . The method of claim 1 , wherein the γc-cytokine-mediated disease is selected from the group consisting of myasthenia gravis, inflammatory bowel disease, CD4-leukemia, CD8-leukemia, LGL-leukemia, systemic lupus erythematosis, Sjögren's syndrome, Wegener's granulomatosis, Celiac disease, Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus, psoriasis, multiple sclerosis, uvietis, inflammation of the eye, and graft-versus-host disease (GvHD).
4 . The method of claim 1 , wherein the nucleotide sequence is selected from the group consisting of dsDNA, ssDNA, dsRNA, and ssRNA.
5 . The method of claim 1 , wherein the nucleotide sequence further comprises a sequence encoding a signal peptide.
6 . A method of treating an HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) associated disease, the method comprising administering to a subject in need thereof the pharmaceutical composition of claim 1 .
7 . The method of claim 6 , wherein the HAM/TSP associated disease is selected from the group consisting of Adult T-cell Leukemia (ATL), HTLV-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), and other non-neeoplastic inflammatory diseases associated with HTLV such as uveitis (HU), arthropathy, pneumopathy, dermatitis, exocrinopathy, and myositis.
8 . A method of treating an inflammatory respiratory disease, the method comprising administering to a subject in need thereof the pharmaceutical composition of claim 1 .
9 . The method of claim 8 , wherein the inflammatory respiratory disease is selected from the group consisting of asthma, sinusitis, hay fever, bronchitis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, acute and chronic otitis, and lung fibrosis.
10 . A method of treating a cosmetic condition, the method comprising administering to a subject in need thereof the pharmaceutical composition of claim 1 .
11 . The method of claim 10 , wherein the cosmetic disease is selected from the group consisting of acne, hair loss, sunburn, nail maintenance, and appearance of aging.
12 . A genetic construct comprising:
a nucleotide sequence encoding a therapeutic composite peptide; and
at least one regulatory element, wherein the at least one regulatory element is configured to regulate expression of the therapeutic composite peptide;
wherein the therapeutic composite peptide inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor, and wherein the therapeutic composite peptide comprises a region 1-20 amino acids in length that aligns with a corresponding region of a single target ligand or receptor.
13 . The genetic construct of claim 12 , wherein the genetic construct is DNA.
14 . The genetic construct of claim 12 , wherein the genetic construct is RNA.
15 . The genetic construct of claim 12 , wherein the family of cytokines is selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines.
16 . The genetic construct of claim 15 , wherein the γc-family of cytokines consists of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, the IL-6 family of cytokines consists of IL-6, IL-11, CNTF, CT-1, OSM, LIF, and IL-27, and the IL-17 family of cytokines consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F.
17 . The genetic construct of claim 12 , wherein the single target ligand or receptor is of any one of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, and SEQ ID NO:161.