Potent compstatin analogs
AssigneeThe Trustees of the University of Pennsylvania
InventorsJohn D. LAMBRIS, Madan Katragadda
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Abstract
Compounds comprising peptides and peptidomimetics 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. Methods of making and using the compounds are also disclosed.
Claims20
A compound that inhibits complement activation, comprising a peptide having a sequence:
- (SEQ ID NO:
- 26)
- Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa3-Gly-Xaa4-His-
- Arg-Cys-Xaa5;
- wherein:
- Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile;
- Xaa2 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp, with the proviso that, if Xaa3 is Trp, Xaa2 is the analog of 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;
- Xaa5 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide comprising Thr-Asn or Thr-Ala, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly or Asn optionally is replaced by —NH2;
- and
- the two Cys residues are joined by a disulfide bond.
The compound of claim 22, wherein the additional peptide component is an albumin binding peptide or albumin binding small molecule.
A method of making a compound that inhibits complement activation, wherein the compound comprises a peptide having a sequence:
- (SEQ ID NO:
- 26)
- Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa3-Gly-Xaa4-His-
- Arg-Cys-Xaa5;
- wherein:
- Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile;
- Xaa2 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp, with the proviso that, if Xaa3 is Trp, Xaa2 is the analog of 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;
- Xaa5 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide comprising Thr-Asn or Thr-Ala, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly or Asn optionally is replaced by —NH2;
- wherein the method comprises synthesizing the peptide by condensation of the amino acid residues or analogs thereof, or expressing a polynucleotide encoding the peptide.
A method of inhibiting complement activation in or on a medium in which complement activation is occurring, comprising contacting the medium with a complement inhibitor, wherein the complement inhibitor comprises a peptide having a sequence:
- (SEQ ID NO:
- 26)
- Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa3-Gly-Xaa4-His-
- Arg-Cys-Xaa5;
- wherein:
- Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile;
- Xaa2 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp, with the proviso that, if Xaa3 is Trp, Xaa2 is the analog of 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;
- Xaa5 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide comprising Thr-Asn or Thr-Ala, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly or Asn optionally is replaced by —NH2;
- and
- the two Cys residues are joined by a disulfide bond.
Dependencies are inferred from the claim text.