Modulation of complement activity
The present invention provides modulators of complement activity. Also provided are methods of utilizing such modulators as therapeutics.
1. A peptide selected from the group consisting of SEQ ID Nos: 1-201 and 211.
2. The polypeptide of claim 1 , further comprising a bridging moiety between two amino acids.
3. The polypeptide of claim 2 , wherein said bridging moiety comprises a structure selected from the group consisting of structures I-XIX;
wherein each X is independently N or CH, such that no ring contains more than 2 N; each Z is independently a bond, NR, O, S, CH 2 , C(O)NR, NRC(O), S(O) v NR, NRS(O) v ; each m is independently selected from 0, 1, 2, and 3; each v is independently selected from 1 and 2;
each R is independently selected from H and C 1 -C 6 ; and each bridging moiety is connected to the polypeptide by independently selected C 0 -C 6 spacers.
4. The polypeptide of claim 2 , wherein the bridging moiety comprises a feature selected from the group consisting of a disulfide bond, an amide bond (lactam), a thioether bond, an aromatic ring, an unsaturated aliphatic hydrocarbon chain, a saturated aliphatic hydrocarbon chain and a triazole ring.
5. The polypeptide of claim 1 , wherein the polypeptide comprises a cyclic loop, wherein the cyclic loop is of a length selected from the group consisting of 1 amino acid, 2 amino acids, 3 amino acids, 4 amino acids, 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9, amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids and 16 amino acids.
6. The polypeptide of claim 4 , wherein said feature comprises an aromatic ring and wherein said bridging moiety is formed by reaction with a poly(bromomethyl)benzene.
7. The polypeptide of claim 6 , wherein the poly(bromomethyl)benzene is selected from the group consisting of 1,2-bis(bromomethyl)benzene, 1,3-bis(bromomethyl)benzene and 1,4-bis(bromomethyl)benzene.
8. The polypeptide of claim 7 wherein the reagent is 1,3-bis(bromomethyl)benzene.
9. The polypeptide of claim 4 , wherein said feature comprises an aromatic ring and wherein said bridging moiety is produced by reaction with a compound selected from the group consisting of 2,6-bis(bromomethyl)pyridine, (E)-1,4-dibromobut-2-ene and 1,2-bis(bromomethyl)-4-alkylbenzene.
10. The polypeptide of claim 1 , wherein said polypeptide is selected from the group consisting of SEQ ID NOs 177, 184, and 194.
11. The polypeptide of claim 10 , wherein said polypeptide comprises SEQ ID NO: 177.
12. The polypeptide of claim 10 , wherein said polypeptide comprises SEQ ID NO: 184.
13. The polypeptide of claim 10 , wherein said polypeptide comprises SEQ ID NO: 194.
14. A composition comprising the polypeptide of any of claims 1 , 10 , and 11 - 13 and an acceptable carrier or excipient.
15. The composition of claim 14 comprising an excipient, wherein said excipient comprises a pharmaceutically acceptable excipient.
16. A method of inhibiting C5 cleavage in a cellular system, said method comprising contacting said cellular system with the composition of claim 15 .
17. The method of claim 16 , wherein said polypeptide inhibits the cleavage of C5 with an IC 50 of less than 50 nM.
18. The method of claim 16 , wherein said cellular system is a human subject.
19. The method of claim 18 , wherein said human subject comprises a complement-related disease, disorder and/or condition.
20. The method of claim 19 , wherein said complement-related disease, disorder and/or condition is selected from the group consisting of an inflammatory indication, a wound, an injury, an autoimmune disease, a vascular indication, a neurological indication, a kidney-related indication, an ocular disease, paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.