Modulators of complement activity

1. A polypeptide of the formula R 1 -Xaa0-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-R 2 (SEQ ID NO: 212), wherein:

a. R 1 is absent or an acetyl group;

b. Xaa0 is absent or selected from the group consisting of norvaline and Ala;

c. Xaa1 is Cys;

d. Xaa2 is phenylglycine;

e. Xaa3 is Thr;

f. Xaa4 is selected from 7-azatryptophan and Trp;

g. Xaa5 is Glu;

h. Xaa6 is selected from the group consisting of Tyr, Phe, 4-fluorophenylalanine, and O-methyl-tyrosine;

i. Xaa7 is selected from the group consisting of Pro, N-methyl-serine, and N-methyl-alanine;

j. Xaa8 is selected from the group consisting of His and Ala;

k. Xaa9 is Cys;

l. Xaa10 is absent or selected from the group consisting of norvaline, and Ala;

m. Xaa11 is absent or Pro;

n. Xaa12 is absent or is norvaline; and

o. R 2 is absent or —NH 2 .

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, CH2, C(O)NR, NRC(O), S(O)vNR, 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 C1-C6; and each bridging moiety is connected to the polypeptide by independently selected C0-C6 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 2 , wherein the bridging moiety joins residue Xaa1 and Xaa9.

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 1 , wherein said polypeptide is selected from the group consisting of SEQ ID NOs 9, 23, 31, 35, 36, 38, 39, 41-44, 46, 48, 51, 53, and 55.

8. A composition comprising the polypeptide of claim 1 and an acceptable carrier or excipient.

9. A method of preparing a C5 inhibitor polypeptide, the method comprising synthesizing the C5 inhibitor polypeptide according to the formula R 1 -Tbg-Tyr-Xaa0-Glu-R 2 , wherein:

R 1 comprises a polypeptide;

Xaa0 is selected from Trp and 7-azatryptophan; and

R 2 comprises a polypeptide; and

isolating the C5 inhibitor polypeptide.

10. The method of claim 9 , wherein the C5 inhibitor polypeptide is prepared by solid phase synthesis.

11. The method of claim 9 , wherein the C5 inhibitor polypeptide is cyclized by incorporation of a bridging moiety between two amino acids.

12. The method of claim 11 , wherein the bridging moiety is incorporated between two amino acid residues of R 1 .

13. The method of claim 12 , wherein R 1 comprises an amino acid sequence according to the formula Xaa1-Val-Glu-Arg-Phe-Xaa2, wherein the bridging moiety is incorporated between Xaa1 and Xaa2, and wherein:

Xaa1 and Xaa2 are Cys; or

Xaa1 is Lys and Xaa2 is Asp.

14. The method of claim 9 , 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.

15. The method of claim 9 , wherein R 2 comprises an amino acid sequence according to the formula Tyr-Pro-Xaa3-Xaa4, wherein:

Xaa3 is absent or selected from the group consisting of phenylglycine, D-phenylglycine, and cyclohexylglycine; and

Xaa4 is absent or selected from the group consisting of norvaline and Lys.

16. The method of claim 15 , wherein R 2 comprises a C-terminal Lys.

17. The method of claim 16 , wherein the C-terminal Lys comprises N-ε-caprylic lysine, N-ε-capryl lysine, N-ε-lauryl lysine, N-ε-palmitoyl lysine, N-ε-(PEG2-γ-glutamic acid-N-α-octadecanedioic acid) lysine, N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl)lysine, or N-ε-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-lysine.

18. A method of assessing a compound for C5 binding, the method comprising:

introducing the compound to a solution of C5 and a C5 binding polypeptide, wherein the C5 binding polypeptide comprises an amino acid sequence according to SEQ ID NO: 1-55, 57-59, 139-156, 158-175, 177, 178, 180-185, 187, 189-201, or 211; and

analyzing the solution for evidence of dissociation between C5 and the C5 binding polypeptide.

19. The method of claim 18 , wherein the C5 binding polypeptide is fluorescently labeled.

20. The method of claim 19 , wherein analyzing the solution for evidence of dissociation comprises analyzing the solution for changes in fluorescence polarization.