CA2833202C — Compstatin analogs with improved activity

USPTO Abstract

Compounds comprising peptides and peptidomimetics capable of binding the C3 protein and inhibiting complement activation are disclosed. These compounds display improved complement activation-inhibitory activity as compared with currently available compounds. Isolated nucleic molecules encoding the peptides are also disclosed. Also disclosed is a method for making the compounds and use of such compounds, such as artificial organ, artificial implant or tubing, coated with a compound of the invention that inhibits complement activation. A method for making the compounds is disclosed which includes synthesizing the peptide by condensation of the amino acid residues or analogs thereof or comprising expressing a polynucleotide encoding the peptide or a concatemer of the peptide, which is post-translationally cleaved to form the peptdide. Also disclosed are compounds comprising a peptide having a sequence: Xaa1 - Xaa2 - Cys - Val - Xaa3 - Gln -Asp - Trp Gly - Xaa4 - His - Arg - Cys - Xaa5 - Xaa6 - Xaa7 (SEQ ID NO:15); wherein: Xaa1 is missing or is Gly; Xaa2 is Ile, Val, Leu, Ac-lle, Ac-Val, Ac-Leu or together with Xaa1 is dipeptide Gly-lle; Xaa3 is Trp or an analog of Trp that comprises a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components; Xaa4 is His, Ala, Phe or Trp; Xaa5 is L-Thr, D-Thr, Ile, Val, Gly, or together with Xaa6 and Xaa7 is tripeptide Thr-Ala-Asn; Xaa6 is missing or is Ala; and Xaa7 is missing or is Asn.