HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site
HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site
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DOI：
10.1021/cb600303y
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Arnold, Eddy
中科院分区：
文献类型：
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作者：
Himmel, Daniel M.;Sarafianos, Stefan G.;Arnold, Eddy
人类免疫缺陷病毒1型(HIV-1)耐药变种的迅速出现限制了抗获得性免疫缺陷综合征(AIDS)治疗的疗效，需要针对新结合位点的新的先导化合物。我们测定了HIV-1逆转录酶(RT)与HIV-1 RT核糖核酸酶H(RNH)抑制剂(RNHI)二羟基苯甲酰肼(DHBNH)络合的3.15埃分辨晶体结构。DHBNH对多种HIV-1RT耐药突变株有效。虽然DHBNH对RT催化的DNA合成的大部分方面几乎没有影响，但在相对较高的浓度下，它确实抑制了RNA启动的DNA合成。虽然主要是RNHI，但DHBNH在聚合酶活性位点和非核苷RT抑制物(NNRTI)结合口袋附近的一个新的位点上，与RNH活性部位相距50埃。当DHBNH结合时，Tyr181和Tyr188都保持在未连接的HIV-1 RT中看到的构象。DHBNH与保守的残基(Asp186，Trp229)相互作用，并与几个不太保守的残基的骨架有大量的相互作用。在此结构的基础上，我们设计了与NNRTI结合口袋相互作用的取代DHBNH衍生物。这些化合物抑制RT的聚合酶和RNH活性。
The rapid emergence of drug-resistant variants of human immunodeficiency virus, type 1 (HIV-1), has limited the efficacy of anti-acquired immune deficiency syndrome (AIDS) treatments, and new lead compounds that target novel binding sites are needed. We have determined the 3.15 angstrom resolution crystal structure of HIV-1 reverse transcriptase (RT) complexed with dihydroxy benzoyl naphthyl hydrazone (DHBNH), an HIV-1 RT RNase H (RNH) inhibitor (RNHI). DHBNH is effective against a variety of drug-resistant HIV-1 RT mutants. While DHBNH has little effect on most aspects of RT-catalyzed DNA synthesis, at relatively high concentrations it does inhibit the initiation of RNA-primed DNA synthesis. Although primarily an RNHI, DHBNH binds > 50 angstrom away from the RNH active site, at a novel site near both the polymerase active site and the non-nucleoside RT inhibitor (NNRTI) binding pocket. When DHBNH binds, both Tyr181 and Tyr188 remain in the conformations seen in unliganded HIV-1 RT. DHBNH interacts with conserved residues (Asp186, Trp229) and has substantial interactions with the backbones of several less well-conserved residues. On the basis of this structure, we designed substituted DHBNH derivatives that interact with the NNRTI-binding pocket. These compounds inhibit both the polymerase and RNH activities of RT.