Claims for Patent: 9,169,307

Summary for Patent: 9,169,307

Title:	Potent compstatin analogs
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.
Inventor(s):	Lambris; John D. (Bryn Mawr, PA), Katragadda; Madan (Ypsilanti, MI)
Assignee:	The Trustees of the University of Pennsylvania (Philadelphia, PA)
Application Number:	13/007,196
Patent Claims:	1. A compound that inhibits complement activation, comprising a peptide having a sequence: TABLE-US-00011 (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 an analog of Trp comprising 5-fluoro- or 6-fluoro-l-tryptophan, or a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan, or a lower alkanoyl substituent at the 1 position of tryptophan; 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 --NH.sub.2; and the two Cys residues are joined by a disulfide bond. 2. The compound of claim 1, wherein: (a) Xaa2 participates in a nonpolar interaction with C3; (b) Xaa3 participates in a hydrogen bond with C3; or (c) Xaa2 participates in a nonpolar interaction with C3, and Xaa3 participates in a hydrogen bond with C3. 3. The compound of claim 1, wherein the analog of Trp of Xaa2 is 5-methoxytryptophan or 5-methyltryptophan. 4. The compound of claim 1, wherein the analog of Trp of Xaa2 is 1-methyltryptophan or 1-formyltryptophan. 5. The compound of claim 1, wherein the analog of Trp of Xaa3 comprises a halogenated tryptophan. 6. The compound of claim 5, wherein the halogenated tryptophan is 5-fluoro-l-tryptophan, or 6-fluoro-l-tryptophan. 7. The compound of claim 1, wherein Xaa4 is Ala. 8. The compound of claim 1, wherein Xaa2 comprises a lower alkanoyl or lower alkyl substituent at the 1 position of tryptophan, Xaa3 optionally comprises a halogenated tryptophan and Xaa4 is Ala. 9. The compound of claim 8, wherein Xaa2 is 1-methyltryptophan or 1-formyltryptophan and Xaa3 optionally comprises 5-fluoro-l-tryptophan. 10. The compound of claim 1, wherein the compound is PEGylated. 11. The compound of claim 1, further comprising an additional peptide component that extends the in vivo retention of the compound. 12. The compound of claim 11, wherein the additional peptide component is an albumin binding peptide. 13. A method of making a compound that inhibits complement activation, wherein the compound comprises a peptide having a sequence: TABLE-US-00012 (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 an analog of Trp comprising 5-fluoro- or 6-fluoro-l-tryptophan, or a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan, or a lower alkanoyl substituent at the 1 position of tryptophan; 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 --NH.sub.2; wherein the method comprises synthesizing the peptide by condensation of the amino acid residues or analogs thereof, or expressing a polynucleotide encoding the peptide. 14. The method of claim 13, further comprising cyclizing the peptide through formation of a disulfide bond between the two Cys residues. 15. The method of claim 13, further comprising post-synthesis modification of the compound selected from one or more of (a) acetylation of Xaa1, (b) replacement of the terminal --OH of Xaa4 with --NH.sub.2, (3) PEGylation of the compound and (4) synthesizing the compound with an additional peptide component that extends the in vivo retention of the compound. 16. 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: TABLE-US-00013 (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 an analog of Trp comprising 5-fluoro- or 6-fluoro-l-tryptophan, or a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan, or a lower alkanoyl substituent at the 1 position of tryptophan; 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 --NH.sub.2; and the two Cys residues are joined by a disulfide bond. 17. The method of claim 16, wherein complement activation is inhibited in one or more of: (a) blood or serum; (b) artificial organs or implants; and (c) in physiological fluids during extracorporeal shunting of the fluids. 18. The method of claim 16, wherein the complement activation is inhibited as part of a treatment of a disease or condition in which complement activation contributes to cell damage or tissue injury. 19. The method of claim 16, adapted to design a peptide analog or peptidomimetic or to screen a small molecule library to identify other compounds that inhibit complement activation or compete with the complement inhibitor for binding to C3 or a C3 fragment.