Abstract
Using affinity purified human immunodeficiency virus (HIV) reverse transcriptase the reaction assay conditions were determined. The optimum incorporation of dTMP into the (rA)n(dT)10 template with HIV reverse transcriptase required 6 mM MgCl2 and 80 mM KCl. The template specificity of HIV reverse transcriptase is quite different from those of the human gamma-polymerase-associated reverse transcriptase or avian virus reverse transcriptase. The preferential inhibition of HIV reverse transcriptase as compared to human gamma-reverse transcriptase was observed with several nucleoside analog triphosphates. The Ki values for thymidine triphosphate analogs with HIV reverse transcriptase ranged from 5 to 13 nM with decreasing effectiveness for 3'-fluoro greater than 3'-amino greater than 2',3'-dideoxy greater than 3'-azido groups. This study provides information on the structure activity relationships of the triphosphate analogs inhibitory effects on HIV reverse transcriptase versus human gamma-polymerase-associated reverse transcriptase, and the possible mechanisms of action of 3' azido thymidine and the 2',3'-dideoxynucleosides, and also identifies other nucleoside analogs for possible development as inhibitors of HIV.
Highlights
From the $Department of Pharmacology, Schoolof Medicine, University of North Carolina at Chapel Hill, Chnpel HillN, orth
Of dTMP into the,(dT)lo template with Human immunodeficiency virus (HIV) re- Preliminary studiesof the properties of HIV reverse transcripverse transcriptase required 6 mM MgClz and 80 mM tase, using a partially purified preparation, show that this
The template specificity of HIV reverse transcrip- enzyme appears to be quite different from other virus-assotase is quite different from those of the human y- ciated reverse transcriptases
Summary
Using affinitypurified human immunodeficiencyvi- HIV-associated reverse transcriptase was recently purified rus (HIV)reverse transcriptase the reaction assay con- using immunoaffinity chromatography. The Ki values for thymidine triphosphate analogs with HIV reverse tranappears to be critical for HIV replication, it presents alogical target for the development of selective antiviral compounds. The structure activity relationships of the triphosphate analogs inhibitory effects on HIV reverse transcriptase. The replacement of the 3‘-OH group by hydrogen, fluorine, amino, Human immunodeficiency virus (HIV)’ may be the cause of acquired immune deficiency syndrome (AIDS). Several compounds (3’-N3dThd (l), 2’,3‘-dideoxynucleosides(2) and phosphonoformate (3,4))were found to have selective effects against HIV replication in culture Their actions andselectivity were attributedtotheirpotent activity against virusassociated reverse transcriptase. Azido groups yielded compounds with very potent inhibitory activities against HIV reverse transcriptase.
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