Compstatin analogs for treatment of neuropathic pain
In some aspects, the present invention provides methods of treating a subject in need of treatment for neuropathic pain, the method comprising administering a compstatin analog to the subject. In some embodiments, the compstatin analog is administered parenterally, e.g., intravenously.
1. A method of treating a subject in need of treatment for neuropathic pain, the method comprising:
administering a therapeutically effective amount of a compstatin analog to the subject,
wherein the compstatin analog is a compound that comprises a cyclic peptide having an amino acid sequence:
Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa2*-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO: 6); wherein:
Xaa1 is Ile, Val, Leu, B 1 -Ile, B 1 -Val, B 1 -Leu or a dipeptide comprising Gly-Ile or B 1 -Gly-Ile, and B 1 represents a first blocking moiety;
Xaa2 is 1-methyltryptophan;
Xaa2* is Trp or an analog of Trp;
Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp;
Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by a second blocking moiety B 2 ; and
the two Cys residues are joined by a disulfide bond.
2. The method of claim 1 , wherein the compstatin analog is administered intravenously.
3. The method of claim 1 , wherein the activity of the compstatin analog is at least 100 times as great as the activity of compstatin as measured in an in vitro assay.
4. The method of claim 1 , wherein
Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile.
5. The method of claim 1 , wherein Xaa2* is an analog of Trp having an electronegative substituent on the indole ring and not having increased hydrophobic character relative to Trp.
6. The method of claim 1 , wherein the compstatin analog has the sequence of SEQ ID NO: 28 or 32.
7. The method of claim 1 , wherein the peptide is acetylated at the N-terminus, amidated at the C-terminus, or both acetylated at the N-terminus and amidated at the C-terminus.
8. The method of claim 1 , further comprising: administering an additional therapy for neuropathic pain to the subject, wherein the additional therapy is selected from the group consisting of antidepressants, anticonvulsants, NMDA antagonists, topical anesthetics, opioid analgesics, and sodium channel blockers.
9. The method of claim 1 , wherein Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn is replaced by —NH 2 .