RT Journal Article SR Electronic T1 Activity of Different Bicyclam Derivatives against Human Immunodeficiency Virus Depends on Their Interaction with the CXCR4 Chemokine Receptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 67 OP 73 DO 10.1124/mol.55.1.67 VO 55 IS 1 A1 José A. Esté A1 Cecilia Cabrera A1 Erik De Clercq A1 Sofie Struyf A1 Jo Van Damme A1 Gary Bridger A1 Renato T. Skerlj A1 Michael J. Abrams A1 Geoffrey Henson A1 Arantxa Gutierrez A1 Bonaventura Clotet A1 Dominique Schols YR 1999 UL http://molpharm.aspetjournals.org/content/55/1/67.abstract AB Bicyclams represent a novel class of selective anti-HIV inhibitors 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-chemokine receptor CXCR4, the main coreceptor used by T-cell tropic strains of HIV. Here we describe the interaction of different bicyclam derivatives with CXCR4. A close correlation (r2 = 0.7) was found between the anti-HIV potency of the bicyclams and their ability to inhibit the binding of an anti-CXCR4 monoclonal antibody or the intracellular Ca++ signal induced by the stromal cell-derived factor-1α, the natural ligand of CXCR4. These results indicate that the mechanism of action of bicyclams is primarily mediated by their interaction with CXCR4. The most potent interaction with CXCR4 and thus anti-HIV activity was shown by bicyclam analogs with cyclam rings composed of fourteen members that are linked by an aromatic (phenyl) bridge. Elucidating the structural requirements for receptor interaction and the site(s) of interaction of bicyclams with CXCR4 will aid in the understanding of HIV-cell fusion.