Modulation of complement activity
The present invention provides modulators of complement activity. Also provided are methods of utilizing such modulators as therapeutics.
1. A C5 inhibitor polypeptide of the formula R 1 -Tbg-Tyr-Xaa0-Glu-R 2 , wherein:
R 1 comprises a polypeptide;
Xaa0 is selected from the group consisting of Trp and azaTrp; and
R 2 comprises a polypeptide.
2. The C5 inhibitor polypeptide of claim 1 , wherein the polypeptide of R 1 comprises an N-terminal acetyl group.
3. The C5 inhibitor polypeptide of claim 2 , wherein the polypeptide of R 1 comprises from about 3 amino acids to about 7 amino acids.
4. The C5 inhibitor polypeptide of claim 3 , wherein the polypeptide of R 1 comprises the formula Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7, wherein:
Xaa1 is Cys or absent;
Xaa2 is Val, Tbg, or is absent;
Xaa3 is Glu, Nvl, or is absent;
Xaa4 is selected from the group consisting of Arg, Cys, and Ser, or is absent;
Xaa5 is Phe or Tyr;
Xaa6 is Cys or Glu; and
Xaa7 is Asp or Asn.
5. The C5 inhibitor polypeptide of claim 1 , wherein the polypeptide of R 2 comprises a C-terminal —NH 2 .
6. The C5 inhibitor polypeptide of claim 1 , wherein the polypeptide of R 2 comprises from about 1 to about 4 amino acids.
7. The C5 inhibitor polypeptide of claim 6 , wherein the polypeptide of R 2 comprises the formula Xaa8-Xaa9-Xaa10-Xaa11, wherein:
Xaa8 is selected from the group consisting of Trp, Tyr, Phe, 2-naphthylalanine, and meta-chloro homophenylalanine;
Xaa9 is selected from the group consisting of Pro, N-methyl-Gly, and Ala, or is absent;
Xaa10 is selected from the group consisting of cyclohexylglycine and norvaline, or is absent; and
Xaa11 is selected from the group consisting of norvaline and N-methyl-serine, or is absent.
8. The C5 inhibitor polypeptide of claim 1 comprising a bridging moiety between two amino acids.
9. The C5 inhibitor polypeptide of claim 8 , wherein the 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.
10. The C5 inhibitor polypeptide of claim 8 , 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.
11. The C5 inhibitor polypeptide of claim 8 , wherein the bridging moiety is formed by reaction with a poly(bromomethyl)benzene.
12. The polypeptide of claim 1 , wherein said polypeptide is conjugated to a hydrophilic polymer.
13. The polypeptide of claim 12 , wherein the hydrophilic polymer is selected from the group consisting of polyalkylene oxide homopolymers, polypropylene glycols, polyoxyethylenated polyols and copolymers thereof.
14. The polypeptide of claim 12 , wherein the hydrophilic polymer comprises polyethylene glycol (PEG).
15. The polypeptide of claim 1 comprising at least one lipid moiety.
16. The polypeptide of claim 1 , wherein said polypeptide is conjugated to an albumin-binding polypeptide, wherein the albumin-binding polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 202-204.
17. The polypeptide of claim 1 , wherein said polypeptide is conjugated to a cell penetrating polypeptide, wherein the cell penetrating polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 205-210.
18. A method of treating a complement-related disease, disorder, or condition in a subject, the method comprising administering the polypeptide of claim 1 to the subject.
19. The method of claim 18 , wherein the complement-related disease, disorder, or condition comprises hemolysis.
20. The method of claim 19 , wherein the hemolysis is caused by thrombin-induced complement activation.
21. The method of claim 18 , wherein the complement-related disease, disorder, 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.