Abstract
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.
Footnotes
- Received April 29, 1998.
- Accepted October 26, 1998.
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Send reprint requests to: Dr. José A. Esté, Fundació irsiCaixa, Retrovirology Laboratory, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain. E-mail:jaeste{at}ns.hugtip.scs.es
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This work was supported in part by the Biomedical Research Program of the European Commission and by grants from the Spanish Fondo de Investigación Sanitaria (FIS) project 98/0868, the Fundació irsiCaixa, and from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO), the Belgian Geconcerteerde Onderzoekacties (GOA) and the Janssen Research Foundation.
- The American Society for Pharmacology and Experimental Therapeutics
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