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 inhibitors with pot ent activity against T-cell tropic strains of HIV. The prototype compound, the bicyclam AMD3100, has an EC50 of I to 10 ng/ml against different strain s of HIV-I, including clinical isolates. AMD3100 was shown to interact with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-cell tropi c strains of HIV. Here we describe the interaction of different bicyclam de rivatives with CXCR4. A close correlation (r(2) = 0.7) was found between th e anti-HIV potency of the bicyclams and their ability to inhibit the bindin g of an anti-CXCR4 monoclonal antibody or the intracellular Ca++ signal ind uced by the stromal cell-derived factor-1 alpha, the natural ligand of CXCR 4. These results indicate that the mechanism of action of bicyclams is prim arily mediated by their interaction with CXCR4. The most potent interaction with CXCR4 and thus anti-HIV activity was shown by bicyclam analogs with c yclam rings composed of fourteen members that are linked by an aromatic (ph enyl) bridge. Elucidating the structural requirements for receptor interact ion and the site(s) of interaction of bicyclams with CXCR4 will aid in the understanding of HIV-cell fusion.