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Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

机译：Carbovir Triphosphate对HIV-1 RT抑制和耐药的分子机制的见解

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摘要

Abacavir (1592U89, or Ziagen) is powerful and selective inhibitor of HIV-1 viral replication that has been approved by the FDA for treatment of acquired immunodeficiency syndrome. Abacavir is metabolized to the active compound carbovir triphosphate (CBVTP). This compound is a guanosine analogue containing a 2',3'-unsaturation in its planar carbocyclic deoxyribose ring thaqt acts on HIV-1 reverse transcriptase (RT~(WT)) as a molecular target, resulting in chain termination of DNA synthesis. A single amino acid change from methionine 184 to valine in HIV-1 RT (RT~(M184V)) has been observed clinically in response to abacavir treatment. The ability of the natural substrate, dGTP, or CBTRP to be utilized during DNA- and RNA-directed polymerization by RT~(WT) and RT~(M184V), suggesting that this mutation confers resistance at the level of CBVMP incorporation. The relatively low incorporation efficiency for RT~(WT) was unanticipated considering earlier studies showing that the triphosphate form of a thymidine nucleoside analogue containing a planar 2',3'-unsaturated ribose ring, D4TTP, was incorporated with high efficiency relative to the natural substrate, dTTP. The difference may be related to the isosteric replacement of oxygen in the deoxyribose ring with carbon. This hypothesis was tested by synthesizing and evaluating D4GTP (the planar 2',3'-unsaturated deoxyribose guanosine analogue that is complementary to D4TTP). In contrast to CBVTP, D4GTP was found to be an excellent substrate for RT~(WT) and no relationships for nucleoside-based inhibitors. In this work, we illustrate how an understanding of the molecular mechanism of inhibition and drug resistance led to the discovery of a novel prodrug of D4G. This compound shows promise as a potent antiviral especially with the drug resistant M184V HIV-1 RT that is so often encountered in a clinical setting.
机译：阿巴卡韦（1592U89，或Ziagen）是一种强大的选择性HIV-1病毒复制抑制剂，已被FDA批准用于治疗获得性免疫缺陷综合症。阿巴卡韦被代谢成活性化合物卡波韦三磷酸（CBVTP）。该化合物是鸟苷类似物，在其平面碳环脱氧核糖环环中含有2'，3'-不饱和基团，作用于作为分子靶标的HIV-1逆转录酶（RT_（WT）），导致DNA合成的链终止。临床上已观察到响应阿巴卡韦治疗的HIV-1 RT（RT〜（M184V））中单个氨基酸从甲硫氨酸184变为缬氨酸。天然底物，dGTP或CBTRP在RT〜（WT）和RT〜（M184V）指导的DNA和RNA定向聚合反应中被利用的能力，表明该突变赋予CBVMP掺入水平抗性。考虑到较早的研究表明，三磷酸形式的胸腺嘧啶核苷类似物含有平面的2'，3'-不饱和核糖环D4TTP，相对于天然的而言，RT〜（WT）的掺入效率相对较低，这是无法预料的底物，dTTP。所述差异可能与用碳等价地将脱氧核糖环中的氧等位取代。通过合成和评估D4GTP（与D4TTP互补的平面2'，3'-不饱和脱氧核糖鸟苷类似物）来检验该假设。与CBVTP相反，D4GTP是RT〜（WT）的优良底物，与基于核苷的抑制剂没有任何关系。在这项工作中，我们举例说明了对抑制和耐药性分子机制的了解如何导致了D4G新型前药的发现。该化合物显示出作为强效抗病毒药的前景，尤其是在临床环境中经常遇到的耐药M184V HIV-1 RT方面。

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