title: 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.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Miho
authors.initials: M
authors.lastname: Fujisawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hiramatsu
authors.forename: Makiko
authors.initials: M
authors.lastname: Mizumoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D009842:Oligopeptides; D019718:Receptors, CXCR4; D003094:Collagen; C116977:T140 peptide