Inhibitors of HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity.
Inhibitors of HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity.
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DOI：
10.3390/biology1030521
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发表时间：
2012-10-19
期刊：
影响因子：
4.2
通讯作者：
Parniak MA
中科院分区：
文献类型：
--
作者：
Ilina T;Labarge K;Sarafianos SG;Ishima R;Parniak MA
HIV-1酶逆转录酶（RT）是抗病毒药物开发的主要靶标，目前FDA批准的抗HIV感染治疗药物中有一半以上靶向该酶的DNA聚合酶活性。HIV-1 RT是一种多功能酶，具有RNA和DNA依赖性聚合酶活性，沿着核糖核酸酶H（RNase H）活性。后者负责在第一链DNA合成期间降解病毒基因组RNA模板，以允许完成逆转录和病毒dsDNA。虽然RT的RNA酶H活性已被证明是病毒感染性所必需的，但目前使用的所有针对RT的药物都抑制该酶的聚合酶活性;没有靶向RNA酶H。在过去的十年中，对临床使用的抗逆转录病毒药物耐药的HIV变体的日益流行刺激了针对不同于当前药物靶向的HIV复制阶段的抑制剂的研究。HIV RNA酶H就是这样一个新的靶点，在过去的几年里，在鉴定和表征新的RNA酶H抑制剂药效团方面取得了重大进展。在这篇综述中，我们主要集中在最有效的低微摩尔效力的化合物，因为这些提供了进一步发展的逻辑基础。我们还讨论了为什么HIV RNA酶H一直是抗逆转录病毒药物开发的困难目标。
HIV-1 enzyme reverse transcriptase (RT) is a major target for antiviral drug development, with over half of current FDA-approved therapeutics against HIV infection targeting the DNA polymerase activity of this enzyme. HIV-1 RT is a multifunctional enzyme that has RNA and DNA dependent polymerase activity, along with ribonuclease H (RNase H) activity. The latter is responsible for degradation of the viral genomic RNA template during first strand DNA synthesis to allow completion of reverse transcription and the viral dsDNA. While the RNase H activity of RT has been shown to be essential for virus infectivity, all currently used drugs directed at RT inhibit the polymerase activity of the enzyme; none target RNase H. In the last decade, the increasing prevalence of HIV variants resistant to clinically used antiretrovirals has stimulated the search for inhibitors directed at stages of HIV replication different than those targeted by current drugs. HIV RNase H is one such novel target and, over the past few years, significant progress has been made in identifying and characterizing new RNase H inhibitor pharmacophores. In this review we focus mainly on the most potent low micromolar potency compounds, as these provide logical bases for further development. We also discuss why HIV RNase H has been a difficult target for antiretroviral drug development.