Fletcher R S, Syed K, Mithani S, Dmitrienko G I, Parniak M A
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis- Jewish General Hospital, Montreal, Quebec, Canada.
Biochemistry. 1995 Apr 4;34(13):4346-53. doi: 10.1021/bi00013a025.
Researchers at the National Cancer Institute first recognized the anti-HIV potential of the carboxanilide compound oxathiin carboxanilide (UC84) [Bader, J. P., et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 6740-6744]. We have compared the inhibitory effect of UC84 and a second-generation thiocarboxanilide derivative, UC38, on HIV-1 reverse transcriptase (RT) RNA-dependent DNA polymerase activity. UC38 was a much better inhibitor (IC50 = 0.8 microM) than UC84 (IC50 = 4.3 microM). Inhibition by UC84 was competitive with respect to primer/template (P/T), whereas that by UC38 was uncompetitive. Both compounds were mixed noncompetitive inhibitors with respect to deoxynucleoside triphosphate (dNTP). Both compounds protected RT from irreversible photoinactivation by an azido derivative of nevirapine, implying that UC84 and UC38 bind to the same region of RT as nevirapine. UC84 photoprotected both free RT and the RT-P/T binary complex, but did not protect the RT-P/T-dNTP ternary complex. In contrast, UC38 completely photoprotected the RT-P/T-dNTP ternary complex, but not free RT or the RT-P/T binary complex. UC84 and UC38 thus appear to bind to different mechanistic forms of RT in the polymerase reaction sequence.
美国国立癌症研究所的研究人员首次认识到羧酰苯胺化合物氧硫杂环戊烷羧酰苯胺（UC84）的抗HIV潜力[巴德，J.P.等人（1991年）《美国国家科学院院刊》88卷，6740 - 6744页]。我们比较了UC84和第二代硫代羧酰苯胺衍生物UC38对HIV - 1逆转录酶（RT）RNA依赖性DNA聚合酶活性的抑制作用。UC38是比UC84更好的抑制剂（IC50 = 0.8微摩尔），而UC84的IC50 = 4.3微摩尔。UC84的抑制作用相对于引物/模板（P/T）是竞争性的，而UC38的抑制作用是非竞争性的。两种化合物相对于脱氧核苷三磷酸（dNTP）都是混合型非竞争性抑制剂。两种化合物都能保护RT免受奈韦拉平叠氮衍生物的不可逆光灭活，这意味着UC84和UC38与奈韦拉平结合在RT的同一区域。UC84能光保护游离RT和RT - P/T二元复合物，但不能保护RT - P/T - dNTP三元复合物。相比之下，UC38能完全光保护RT - P/T - dNTP三元复合物，但不能保护游离RT或RT - P/T二元复合物。因此，UC84和UC38似乎在聚合酶反应序列中与RT的不同机制形式结合。
