Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor

Bicyclams represent a novel class of selective anti-HIV inhibi-tors with potent activity against T-cell tropic strains of HIV. The prototype compound, the bicyclam AMD3100, has an EC50 of 1 to 10 ng/ml against different strains of HIV-1, including clinical isolates. AMD3100 was shown to interact with the CXC-che-mokine receptor CXCR4, the main coreceptor used by T-cell tropic strains of HIV. Here we describe the interaction of differ-ent bicyclam derivatives with CXCR4. A close correlation (r2 5 0.7) was found between the anti-HIV potency of the bicyclams and their ability to inhibit the binding of an anti-CXCR4 mono-clonal antibody or the intracellular Ca11 signal induced by the stromal cell-derived factor-1a, the natural ligand of CXCR4. These results indicate that the mechanism of action of bicy-clams is primarily mediated by their interaction with CXCR4