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Kinetic analysis of inhibition of human immunodeficiency virus type-1 reverse transcriptase by calanolide A

MJ Currens, JM Mariner, JB McMahon and MR Boyd

Laboratory of Drug Discovery Research and Development, National Cancer Institute, Frederick, Maryland, USA.

Calanolide A, first isolated from the tropical rain forest tree Calophyllum lanigerum, is a potent human immunodeficiency virus type-1 (HIV-1) specific reverse transcriptase (RT) inhibitor, broadly active against diverse HIV-1 strains, including nucleoside and nonnucleoside- resistant variants. We examined the biochemical mechanism of inhibition of HIV-1 RT by calanolide A. Two template/primer systems were examined: ribosomal RNA and homopolymeric rA-dT 12-18. Calanolide A inhibited HIV- 1 RT by a complex mechanism involving two calanolide A binding sites. With respect to either deoxynucleotide triphosphate (dNTP) or template/primer binding, one site was competitive and the other was uncompetitive. The data indicated that calanolide A bound near the active site of the enzyme and interfered with dNTP binding. Calanolide A inhibited HIV-1 RT in a synergistic fashion with nevirapine, further distinguishing it from the general class of nonnucleoside RT inhibitors. At certain concentrations, calanolide A bound HIV-1 RT in a mutually exclusive fashion with respect to both the pyrophosphate analog, phosphonoformic acid and the acyclic nucleoside analog 1- ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil. This indicates that calanolide A shares some binding domains with both phosphonoformic acid and 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil, presumably reflecting that it interacts with RT near both the pyrophosphate binding site and the active site of the enzyme.

Volume 279, Issue 2, pp. 652-661, 11/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics.