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基于结构的抗药性人类免疫缺陷病毒非核苷类逆转录酶抑制剂设计

Structure-based design of non-nucleoside reverse transcriptase inhibitors of drug-resistant human immunodeficiency virus.

作者信息

Mao C, Sudbeck E A, Venkatachalam T K, Uckun F M

机构信息

Department of Structural Biology, Hughes Institute, St Paul, MN 55113, USA.

出版信息

Antivir Chem Chemother. 1999 Sep;10(5):233-40. doi: 10.1177/095632029901000502.

Abstract

A computer model of reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1) was used to design thiourea compounds that were predicted to inhibit RT. The RT model was used to approximate how changes in binding pocket shape, volume and chemical properties resulting from residue mutations would affect inhibitor binding. Our lead compound, N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thi ourea (HI-236) was tested against clinically observed non-nucleoside inhibitor (NNI)-resistant mutated strains of HIV. HI-236 was more potent than trovirdine, MKC-442 and zidovudine against the drug-sensitive HIV-1 strain IIIB, 50-100 times more effective than delavirdine or nevirapine and twice as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV-1 strain A17. HI-236 was highly effective against the multidrug-resistant HIV-1 strain RT-MDR containing multiple mutations involving the RT residues 74V, 41L, 106A and 215Y. In general, thiourea compounds such as HI-236 and HI-240 showed better inhibition of drug-resistant strains of HIV-1 than thioalkylbenzyl-pyrimidine compounds such as HI-280 and HI-281. The improved activity of thioureas against RT mutants is consistent with a structural analysis of the NNI binding pocket model of RT. The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, in the following order, from high to low activity; HI-236 (IC50 5 nM), HI-240 (IC50 6 nM), trovirdine (IC50 20 nM), zidovudine (IC50 150 nM), MKC-442 (IC50 300 nM), delavirdine (IC50 400 nM) and nevirapine (IC50 5 microM).

摘要

利用来自1型人类免疫缺陷病毒(HIV-1)的逆转录酶(RT)计算机模型设计了预计可抑制RT的硫脲化合物。该RT模型用于估算由残基突变导致的结合口袋形状、体积和化学性质的变化将如何影响抑制剂结合。我们的先导化合物N-[2-(2,5-二甲氧基苯乙基)]-N'-[2-(5-溴吡啶基)]-硫脲(HI-236)针对临床上观察到的对非核苷类抑制剂(NNI)耐药的HIV突变株进行了测试。HI-236对药物敏感的HIV-1 IIIB株比曲伏定、MKC-442和齐多夫定更有效,比地拉韦定或奈韦拉平有效50至100倍,并且在针对对NNI耐药的Y181C突变HIV-1 A17株方面,其效力是我们最近报道的先导化合物N-[2-(2-氟苯乙基)]-N'-[2-(5-溴吡啶基)]-硫脲(HI-240)的两倍。HI-236对含有涉及RT残基74V、41L、106A和215Y的多个突变的多药耐药HIV-1 RT-MDR株非常有效。总体而言,与硫代烷基苄基嘧啶化合物如HI-280和HI-281相比,硫脲化合物如HI-236和HI-240对HIV-1耐药株表现出更好的抑制作用。硫脲类对RT突变体活性的提高与RT的NNI结合口袋模型的结构分析一致。HI-236对RT-MDR的活性优于所测试的其他抗HIV药物,活性从高到低依次为:HI-236(IC50 5 nM)、HI-240(IC50 6 nM)、曲伏定(IC50 20 nM)、齐多夫定(IC50 150 nM)、MKC-442(IC50 300 nM)、地拉韦定(IC50 400 nM)和奈韦拉平(IC50 5 microM)。

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