Identification of a CXCR4 antagonist, a T140 analog, as an anti-rheumatoid arthritis agent.

Abstract

Several recent papers support the involvement of an interaction between stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor, chemokine receptor CXCR4, in memory T cell migration in the inflamed rheumatoid arthritis (RA) synovium. Analogs of the 14-mer peptide T140 were previously found to be specific CXCR4 antagonists that were characterized as not only HIV-entry inhibitors but also anti-cancer-metastatic agents. In this study, a T140 analog, 4F-benzoyl-TN14003, was proven to inhibit CXCL12-mediated migration of human Jurkat cells and mouse splenocyte in a dose-dependent manner in vitro (IC(50)=0.65 and 0.54 nM, respectively). Furthermore, slow release administration by subcutaneous injection (s.c.) of 4F-benzoyl-TN14003 using an Alzet osmotic pump significantly suppressed the delayed-type hypersensitivity response induced by sheep red blood cells in mice, and significantly ameliorated clinical severity in collagen-induced arthritis in mice. As such, T140 analogs might be attractive lead compounds for chemotherapy of RA.

• Authors: Hirokazu Tamamura, Miho Fujisawa, Kenichi Hiramatsu, Makiko Mizumoto, Hideki Nakashima, Naoki Yamamoto, Akira Otaka, Nobutaka Fujii
• Journal: FEBS letters (FEBS Lett) Vol. 569 Issue 1-3 Pg. 99-104 (Jul 02 2004) ISSN: 0014-5793 [Print] England
• PMID: 15225616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Oligopeptides
• Receptors, CXCR4
• Collagen
• T140 peptide

Topics

• Animals
• Antirheumatic Agents (pharmacology)
• Arthritis, Rheumatoid (chemically induced, drug therapy)
• Cell Movement (drug effects)
• Collagen
• Humans
• Jurkat Cells
• Mice
• Oligopeptides (pharmacology, therapeutic use)
• Receptors, CXCR4 (antagonists & inhibitors)