New thymidine triphosphate analogue inhibitors of human immunodeficiency virus-1 reverse transcriptase.
Several novel imidotriphosphate analogues of thymidine have been synthesized and have been shown to be effective inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). When the alpha,beta-bridging oxygens of thymidine triphosphate (TTP) and 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) were replaced by a nitrogen, the resulting analogues were no longer substrates but instead became competitive inhibitors of HIV-1 RT. The most potent of the alpha,beta-imidotriphosphate derivatives tested was thymidine 5'-[alpha,beta-imido]triphosphate (TMPNPP, 1a). This analogue has a Ki value of 2.4 microM, inhibiting HIV-1 RT 400-fold more potently than it inhibits DNA polymerase I large fragment (Klenow). 3'-Azido-3'-deoxythymidine 5'-[alpha,beta-imido]triphosphate (AZTMPNPP, 1b) gave a Ki value about 10-fold greater than that for TMPNPP, indicating that a 3'-azido substituent decreases the affinity of AZTTP to HIV-1 RT relative to the normal 3'-OH substituent. Dideoxythymidine 5'-[alpha,beta-imido]triphosphate (ddTMPNPP, 1c) was intermediate in potency, giving a Ki value of 15 microM. In contrast, substitution at the beta,gamma-bridging oxygen by nitrogen did not block the enzymatic cleavage of the adjacent alpha,beta-phosphate linkage, and 3'-azidothymidine 5'-[beta,gamma-imido]triphosphate (AZTMPPNP, 1e), the 5'-[beta,gamma-imido]triphosphate analogue of AZTTP, is therefore both a substrate for and a potent inhibitor of HIV-1 RT with an observed Ki value of 87 nM. Further nitrogen substitution of the bridging oxygens in the phosphate chain decreases the inhibitory potency by approximately 10-fold, as in the case of thymidine 5'-[alpha,beta:beta,gamma-diimido]triphosphate (TMPNPNP, 1d).
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Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Bathurst
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Barr
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Kenyon
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D001667:Binding, Competitive; D054306:Dideoxynucleotides; D015497:HIV-1 / Q000201:enzymology*; D015394:Molecular Structure; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D013942:Thymine Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D054306:Dideoxynucleotides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C074905:thymidine 5'-(alpha,beta-imido)triphosphate; C074906:3'-azido-3'-deoxythymidine 5'-(beta,gamma-imido)triphosphate; D015215:Zidovudine; D012194:RNA-Directed DNA Polymerase; C024157:thymidine 5'-triphosphate