Inhibition of human immunodeficiency virus reverse transcriptase by 2′,3′-dideoxynucleoside triphosphates: Template dependence, and combination with phosphonoformate

✍ Scribed by Milbrey C. Starnes; Yung-Chi Cheng

• Book ID: 104631675
• Publisher: Springer
• Year: 1989
• Tongue: English
• Weight: 840 KB
• Volume: 2
• Category: Article
• ISSN: 0920-8569
• DOI: 10.1007/bf00125341

✦ Synopsis

The 2',3'-dideoxynucleoside triphosphates (ddNTPs) are potent substrate analog inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and have clinical utility in the treatment of acquired immunodeticiency syndrome. Several issues regarding the interaction of these compounds with HIV reverse transcriptase were examined. The potency of unsubstituted ddNTPs and the 3'azido analog of dTTP (AZTTP) was influenced by the choice of template. Both compounds were more potent with the complementary homopolymer templates than with gapped duplex DNA, although the K,,, for the competing dNTP was similar with different templates. The K, for AZTTP was greater than for the unsubstituted ddNTPs with either a homopolymer or a gapped duplex DNA template. HIV reverse transcriptase incorporated ddCMP and AZTMP into primed phage ml3 DNA at sites specified for insertion of dCMP and dTMP, respectively. ddCTP was more effkiently utilized as a substrate than was AZTTP. Primer elongation due to base misincorporation was observed in the absence of one dNTP. The combined effect of ddNTPs and the pyrophosphate analog phosphonofor-STARNES AND CHENG mate (PFA) on HIV reverse transcriptase was also examined, and inhibition by PFA in combination with ddTTP or AZTTP was mutually exclusive.