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

FEBS Letters
Hirokazu TamamuraNobutaka Fujii

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.

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Citations

Sep 24, 2009·Inflammatory Bowel Diseases·Iris DotanHanan Guzner-Gur
Dec 14, 2005·Current Opinion in Rheumatology·Ines ColmegnaLuis R Espinoza
Apr 28, 2007·American Journal of Respiratory Cell and Molecular Biology·Jianguo XuMauricio Rojas
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Jan 5, 2012·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Hirokazu Tamamura
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Jun 21, 2014·Expert Opinion on Therapeutic Targets·Amanda VillalvillaGabriel Herrero-Beaumont
Nov 23, 2005·Expert Opinion on Therapeutic Targets·Hirokazu Tamamura, Nobutaka Fujii
Apr 2, 2009·Expert Opinion on Investigational Drugs·Jan A Burger, David J Stewart
Oct 1, 2008·Expert Opinion on Drug Discovery·Hirokazu TamamuraNobutaka Fujii
Jan 31, 2012·Expert Opinion on Investigational Drugs·Amnon PeledJan Burger
Jun 1, 2012·Expert Opinion on Drug Discovery·Chie HashimotoHirokazu Tamamura
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Oct 23, 2012·ChemMedChem·Tetsuo NarumiHirokazu Tamamura

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