Compstatin analogs with improved activity

Patent metadata

Field	Value
Publication number	US-2017190741-A9
Application number	US-201414521075-A
Country	US
Kind code	A9
Filing date	Oct 22, 2014
Priority date	Sep 20, 2002
Publication date	Jul 6, 2017
Grant date	—

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 acid molecules encoding the peptides are also disclosed.

First claim

What is claimed:

1 . A compound that inhibits complement activation, which comprises a peptide having a sequence:

(SEQ ID NO: 15)

Xaa1-Cys-Val-Xaa2-Gln-Asp-Trp-Gly-Xaa3-His-

Arg-Cys-Xaa4;

wherein:
Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile;
Xaa2 is Tip or a peptidic or non-peptidic analog of Trp;
Xaa3 is His, Ala, Phe or Trp;
Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, 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 2 ; and
the two Cys residues are joined by a disulfide bond.

2 . The compound of claim 1 , wherein Xaa1 is Ac-Ile.

3 . The compound of claim 1 , wherein Xaa3 is Ala.

4 . The compound of claim 1 , wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components.

5 . The compound of claim 4 , wherein the analog of Trp is selected from the group consisting of 2-napthylalanine, 1-naphthylalanine, 2-indanylglycine carboxylic acid, dihydrotryptophan and benzoylphenylalanine

6 . The compound of claim 1 , wherein Xaa1 is Ac-Ile, Xaa2 is Trp or an analog of Trp comprising a substituted or unsubstituted indole, naphthyl or dibenzoyl component, Xaa3 is Ala and Xaa4 is L-threonine or D-threonine.

7 . The compound of claim 6 , having a sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13.

8 . The compound of claim 1 , wherein Xaa1 is a dipeptide Gly-Ile, and Xaa 4 is a tripeptide Thr-Ala-Asn.

9 . The compound of claim 8 , comprising a peptide having SEQ ID NO:14.

10 . A compound that inhibits complement activation, comprising a non-peptide or partial peptide mimetic of the compound of claim 1 , wherein the compound binds C3 and inhibits complement activation with at least five-fold greater activity than does a peptide comprising SEQ ID NO:1, under equivalent assay conditions.

11 . An isolated nucleic acid molecule encoding one or more peptides that inhibits complement activation, wherein the peptide comprises a sequence:
Xaa1-Cys-Val-Xaa2-Gln-Asp-Trp-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO:15); wherein: Xaa1 is Ile, Val, Leu, or a dipeptide comprising Gly-Ile; Xaa2 is Trp; Xaa3 is His, Ala, Phe or Trp; and Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, or a tripeptide comprising Thr-Ala-Asn; wherein the two Cys residues are joined by a disulfide bond.

12 . The isolated nucleic acid molecule of claim 11 , encoding a peptide wherein Xaa3 is Ala.

13 . The isolated nucleic acid molecule of claim 12 , encoding a peptide comprising SEQ ID NO:14.

14 . The isolated nucleic acid molecule of claim 13 , encoding a concatemer of two or more of a peptide comprising SEQ ID NO:14, wherein the encoded concatemer is cleavable by hydrazine to form a multiplicity of peptides comprising SEQ ID NO:14.

15 . An expression vector comprising the isolated nucleic acid molecule of claim 11 .

16 . A cell comprising the expression vector of claim 15 .

17 . The cell of claim 16 , which is a bacterial, fungal, plant, insect or mammalian cell.

Assignees

• Univ Pennsylvania

Inventors

• Lambris John D

Classifications

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07K7/08 Primary

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title