Method of designing a peptide and/or peptide derivative for modulating gamma-c-cytokine activity
The γc-family cytokines, Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-7 (IL-7), Interleukin-9 (IL-9), Interleukin-15 (IL-15), and Interleukin-21 (IL-21), are associated with important human diseases, such as leukemia, autoimmune diseases, collagen diseases, diabetes mellitus, skin diseases, degenerative neuronal diseases and graft-versus-host disease (GvHD). Thus, inhibitors of γc-cytokine activity are valuable therapeutic and cosmetic agents as well as research tools. Peptide and/or peptide derivative antagonists based on the consensus γc-subunit binding site to inhibit γc-cytokine activity are described. Also described are peptide and/or peptide derivative antagonists exhibiting Simul-Block activity, and inhibiting the activity of multiple γc-cytokine family members.
1. A method of designing a peptide or peptide derivative configured to modulate γc-cytokine activity, the method comprising the steps of:
using a computer to obtain from an amino acid sequence database amino acid sequences of a γc-box D-helix region of at least two interleukin (IL) proteins; and
assembling the peptide or peptide derivative comprising a sequence comprising partial sequences of the γc-box D-helix regions of the at least two IL proteins, wherein the peptide or peptide derivative sequence comprises 11 to 50 amino acids;
synthesizing by solid-phase peptide synthesis, biological synthesis, or both, the peptide or peptide derivative,
thereby designing the peptide or peptide derivative configured to modulate the activity of one or more γc-cytokines.
2. The method of claim 1 , wherein the sequence comprises consecutive blocks of at least 5 amino acids of the at least two IL protein γc-box D-helix regions.
3. The method of claim 1 , wherein the sequence comprises consecutive blocks of 1-10 amino acids of the at least two IL protein γc-box D-helix regions.
4. The method of claim 1 , wherein the at least two IL protein γc-box D-helix regions are from IL proteins selected from the group consisting of IL-15, IL-2, IL-21, IL-4, IL-9, and IL-7.
5. The method of claim 1 , wherein the peptide or peptide derivative further comprises a conjugate at the N-termini, C-termini, side residues, or a combination thereof.
6. The method of claim 1 , wherein the peptide or peptide derivative further comprises a signal peptide.
7. The method of claim 1 , wherein the peptide comprises the amino acid sequence D/E-F-L-E/Q/N-S/R-X-I/K-X-L/I-X-Q (SEQ ID NO: 2), wherein X denotes any amino acid.
8. The method of claim 7 , wherein the peptide derivative shares 50% identity with a peptide of SEQ ID NO: 2.
9. The method of claim 7 , wherein the peptide derivative shares 90% identity with a peptide of SEQ ID NO: 2.
10. The method of claim 7 , wherein the peptide derivative shares 95% identity with a peptide of SEQ ID NO: 2.
11. The method of claim 7 , wherein the peptide and the peptide derivative have similar physico-chemical properties but distinct biological activities.
12. The method of claim 1 , wherein the peptide comprises the amino acid sequence I K E F L Q R F I—H-I-V-Q-S—I-I-N-T-S(SEQ ID NO: 1) (BNZ-γ).
13. The method of claim 12 , wherein the peptide derivative shares 50% identity with a peptide of SEQ ID NO: 1.
14. The method of claim 12 , wherein the peptide derivative shares 90% identity with a peptide of SEQ ID NO: 1.
15. The method of claim 12 , wherein the peptide derivative shares 95% identity with a peptide of SEQ ID NO: 1.
16. The method of claim 12 , wherein the peptide and the peptide derivative have similar physico-chemical properties but distinct biological activities.
17. The method of claim 1 , wherein the peptide or peptide derivative inhibits the activity of one or more γc-cytokines.
18. The method of claim 17 , wherein the one or more γc-cytokines are selected from the group consisting of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
19. The method of claim 17 , wherein the peptide or peptide derivative inhibits the activity of IL-2, IL-15 and IL-9.
20. The method of claim 17 , wherein the peptide or peptide derivative inhibits the activity of IL-15 and IL-9.
21. The method of claim 1 , wherein the peptide or peptide derivative is used to ameliorate and/or treat a disease selected from the group consisting of a γc-cytokine-mediated disease, an HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) associated disease, and an inflammatory respiratory disease.
22. The method of claim 21 , wherein the γc-cytokine-mediated disease is selected from the group consisting of CD4-leukemia, CDS-leukemia, LGL-leukemia, systemic lupus erythematosus, Sjögren's syndrome, Wegener's granulomatosis, Celiac disease, Hashimoto's thyroiditis, rheumatoid arthritis, inflammatory bowel disease, diabetes mellitus, psoriasis, multiple sclerosis, uveitis, inflammation of the eye, and graft-versus-host disease (GvHD).
23. The method of claim 21 , 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-neoplastic inflammatory diseases associated with HTLV.
24. The method of claim 21 , 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.
25. The method of claim 1 , wherein the peptide or peptide derivative is used for a cosmetic purpose.
26. The method of claim 25 , wherein the cosmetic purpose is selected from the group consisting of treatment of acne, treatment of hair loss, treatment of sunburn, nail maintenance, and reduction in the appearance of aging.