Compstatin analogs
The disclosure describes compstatin analogs and methods of using such analogs for the treatment of complement-related disease and disorder.
1. A compstatin analog comprising the sequence X 1 X 2 X 3 CVX 4 QDWGX 5 HRCT, wherein X 1 and X 2 may or may not be present, if X 1 and/or X 2 are present X 1 is selected from S, W, R, E or N and X 2 is selected from S, W, R or N; wherein X 3 is selected from W, meW, R, I or L, wherein X 4 is W, meW, Nmw, V, Y or a non-natural amino acid analog of alanine; wherein X 5 is A or a non-natural amino acid analog of alanine; wherein the analog is acetylated at the N-terminus and amidated at the C-terminus; and wherein the compstatin analog is capable of binding mouse, rat or human C3.
2. A compstatin analog of claim 1 , wherein X 1 and X 2 comprise a diserine extension.
3. The compstatin analog of claim 1 , wherein the compound is capable of binding rat or mouse C3.
4. The compstatin analog of claim 1 , wherein X 3 is R, and X 4 is W.
5. The compstatin analog of claim 4 , wherein the compound is capable of binding rat or mouse C3.
6. The compstatin analog of claim 1 , wherein the analog comprises a sequence selected from the group consisting of (a) Ac-meWCVWQDWGAHRCT-NH 2 (SEQ ID NO:6), (b) Ac-RCVmeWQDWGAHRCT-NH 2 (SEQ ID NO:7), (c) Ac-WWRCVWQDWGAHRCT-NH 2 (SEQ ID NO:9), (d) Ac-RSICVmeWQDWGAHRCT-NH 2 (SEQ ID NO:10), (e) Ac-RSRCVmeWQDWGAHRCT-NH 2 (SEQ ID NO:11), (f) Ac-SSRCVmeWQDWGAHRCT-NH 2 (SEQ ID NO:12), (g) Ac-ICVmeWQDWG(Nal)HRCT-NH 2 (SEQ ID NO:14); (h) Ac-ICVWQDWG(Nal)HRCT-NH 2 (SEQ ID NO:15), (i) Ac-ICVWQDWG(Rea)HRCT-NH 2 (SEQ ID NO:16); (j) Ac-ICVWQDWG(Aal)HRCT-NH 2 (SEQ ID NO:17); (k) Ac-ICVWQDWG(Sea)HRCT-NH 2 (SEQ ID NO:18); (l) Ac-ERICVWQDWGAHRCT-NH 2 (SEQ ID NO:19), (m) Ac-NNLCVWQDWGAHRCT-NH 2 (SEQ ID NO:20); (n) Ac-NRLCVWQDWGAHRCT-NH 2 (SEQ ID NO:21); (o) Ac-RSICVWQDWGAHRCT-NH 2 (SEQ ID NO:22); (p) Ac-ERICVWQDWG(Nal)HRCT-NH 2 (SEQ ID NO:23); (q) Ac-NNLCVWQDWG(Nal)HRCT-NH 2 (SEQ ID NO:24); (r) Ac-NRLCVWQDWG(Nal)HRCT-NH 2 (SEQ ID NO:25); (s) Ac-RSICVWQDWG(Nal)HRCT-NH 2 (SEQ ID NO:26); (t) Ac-ERICV(Nal)QDWG(Nal)HRCT-NH 2 (SEQ ID NO:27); (u) Ac-NNLCV(Nal)QDWG(Nal)HRCT-NH 2 (SEQ ID NO:28); (v) Ac-NRLCV(Nal)QDWG(Nal)HRCT-NH 2 (SEQ ID NO:29); and (w) Ac-RSICV(Nal)QDWG(Nal)HRCT-NH 2 (SEQ ID NO:30).
7. The compstatin analog of claim 1 , wherein the peptide is cyclized through a disulfide bond between the cysteine residues.
8. A method of using a compstatin analog of claim 1 for treating age-related macular degeneration or other complement system-mediated diseases, comprising contacting an individual in need of treatment with the compstatin analog to inhibit the activation of human or primate C3.
9. The method of claim 8 , wherein the disease is selected from a group consisting of asthma, adult respiratory distress syndrome, hemolytic anemia, rheumatoid arthritis, rejection of xenotransplantation, stroke and heart attack.
10. The method of claim 8 , wherein the compstatin analog inhibits the classical complement pathway.
11. The method of claim 8 , wherein the compstatin analog inhibits the alternative complement pathway.
12. The method of claim 8 , wherein the compstatin analog inhibits both the classical and alternate pathways.
13. The method of claim 8 , wherein the composition is administered intravenously.
14. The method of claim 9 , wherein the composition is administered intravitreally.
15. A composition comprising a compstatin analog of claim 1 and a pharmaceutically acceptable carrier.