15th International AIDS Conference Bangkok, Thailand — July 11-July 16, 2004

Int Conf AIDS. 2004 Jul 11-16;15:Abstract No. LbOrA01

T Murakami¹, A Yoshida¹, S Kumakura², R Tanaka¹, S Mitsuhashi², K Hirose², M Yanaka², N Yamamoto³, Y Tanaka^1
1University of the Ryukyus, Okianwa, Japan; ²Kureha Chemical Industry Co. Ltd, Tokyo, Japan; ³National Institute of Infectious Diseases, Tokyo, Japan

The chemokine receptors CXCR4 and CCR5, are the main coreceptors utilized by HIV-1 clinical isolates, and thus have been considered to be attractive targets for possible intervention of HIV-1 infection. We recently generated KRH-2731-5HCl, a novel orally bioavailable CXCR4 antagonist. Its anti-HIV-1 suppressive activity was tested with various HIV-1 strains including clinical isolates in activated PBMCs in vitro. Inhibition of both SDF-1 alpha binding and its mediated Ca²⁺ signaling were determined using various combinations of chemokines and respective receptor-expressing cells. A set of monoclonal antibodies recognizing various regions on CXCR4 was used to locate the binding site of KRH-2731-5HCl. Its anti-HIV-1 activity in vivo and pharmacokinetic properties were determined in hu-PBL-SCID mice and rats, respectively. KRH-2731-5HCl efficiently inhibited the replication of all X4 and R5X4 HIV-1, but not R5, HIV-1 strains tested (EC₅₀ of 1.0-4.2 nM) in activated PBMCs. The potency of suppression of X4 HIV-1 by KRH-2731-5HCl was approximately 10-fold higher than that of another orally available CXCR4 antagonist, AMD070. KRH-2731-5HCl specifically inhibited both SDF-1 alpha binding to and signaling in CXCR4-expressing cells. The putative binding site was localized to a region consisting of the second and the third extracellular loops of CXCR4. KRH-2731-5HCl successfully suppressed X4 HIV-1 infection in the hu-PBL-SCID mice when administered p.o. in drinking water at an average dose of 10 mg/kg/day for 9 days. In addition, KRH-2731-5HCl did not inhibit generation of antigen-specific antibody- and T cell- immune responses of human in the hu-PBL-SCID mice. The bioavailability of KRH-2731-5HCl was 37% in rats administered orally at a dose of 10 mg/kg. The present data show that KRH-2731-5HCl is a potent and harmless X4 HIV-1 inhibitor in animals, and suggest that it has a therapeutic potential in clinical use.

040711
LbOrA01

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