New Thymidine Triphosphate Analogue Inhibitors of Human Immunodeficiency Virus-1 Reverse Transcriptase

Article abstract of DOI:10.1021/jm00089a002

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 α,β-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 α,β-imidotriphosphate derivatives tested was thymidine 5'-<α,β-imido>triphosphate (TMPNPP, 1a).This analogue has a K_i value of 2.4 μM inhibiting HIV-1 RT 400-fold more potently than in inhibits DNA polymerase I large fragment (Klenow). 3'-Azido-3'-deoxythymidine 5'-<α,β-imido>triphosphate (AZTMPNPP, 1b) gave a K_i 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'-<α,β-imido>triphosphate (ddTMPNPP, 1c) was intermediate in potency, giving a K_i value of 15 μM.In contrast, substitution at the β,γ-bridging oxygen by nitrogen did not block the enzymatic cleavage of the adjacent α,β-phosphate linkage, and 3'-azidothymidine 5'-<β,γ-imido>triphosphate (AZTMPPNP, 1e), the 5'-<β,γ-imido>triphosphate analogue of AZTTP, is therefore both a substrate for and a potent inhibitor of HIV-1 RT with an observed K_i 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'-<α,β:β,γ-diimido>triphosphate (TMPNPNP, 1d).