Modified compstatin with peptide backbone and C-terminal modifications
AssigneeThe Trustees of the University of Pennsylvania
InventorsJohn D. Lambris, Hongchang Qu
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Abstract
Compounds comprising peptides capable of binding C3 protein and inhibiting complement activation are disclosed. These compounds display greatly improved complement activation-inhibitory activity as compared with currently available compounds. The compounds comprise compstatin analogs having a constrained backbone at position 8 (glycine) and, optionally, specific substitutions for threonine at position 13.
Claims23
A modified compstatin peptide (ICVVQDWGHHRCT (cyclic C2-C12);
- SEQ ID NO:1), in which the Gly at position 8 is N-methylated to constrain the backbone conformation of the peptide at that location, and comprising one or more additional modifications selected from:
- a) acetylated N-terminus;
- b) Ala instead of His at position 9 of the peptide;
- c) Trp or an analog of Trp instead of Val at position 4 of the peptide;
- d) halogenated Trp at position 7 of the peptide;
- e) Ile, Leu, Nle, N-methyl Thr or N-methyl Ile instead of Thr at position 13 of the peptide;
- and
- f) amidated C-terminus.
A compstatin analog that binds C3 and inhibits complement activation with at least the same potency as compstatin, comprising a peptide having a sequence of SEQ ID NO:2, which is:
- Xaa1a-Xaa1b-Cys-Val-Xaa2-Gln-Asp-Xaa3-Gly-Xaa4-His-Arg-Cys-Xaa5 (cyclic C2-C 12) in which Gly at position 8 is N-methylated to constrain the backbone conformation at that location;
- wherein:
- Xaa1a and Xaa1b together form position 1 of the peptide;
- Xaa1a is missing or is Gly, provided Xaa1b is Ile;
- Xaa1b is Ile, Val, Leu, Ac-Ile, Ac-Val, or Ac-Leu;
- Xaa2 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp;
- Xaa3 is Trp or an analog of Trp comprising a chemical modification to its indole ring wherein the chemical modification increases the hydrogen bond potential of the indole ring;
- Xaa4 is His, Ala, Phe or Trp;
- and
- Xaa5 is Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile, wherein a carboxy terminal —OH of any of the Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile optionally is replaced by —NH2.
Dependencies are inferred from the claim text.