Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1
Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1
复制标题
DOI：
10.1128/aac.01455-09
复制
发表时间：
2010-10-01
影响因子：
4.9
通讯作者：
Perros, Manos
中科院分区：
文献类型：
--
作者：
Corbau, Romuald;Mori, Julie;Perros, Manos
非核苷类逆转录酶抑制剂（NNRTI）是高效抗逆转录病毒治疗（HAART）的关键组成部分，用于治疗人类免疫缺陷病毒1型（HIV-1）。第一批批准的NNRTI的一个主要问题是HIV-1逆转录酶（RT）突变的出现，特别是K103 N和Y181 C，这导致了对整个类别的耐药性。我们采用了一种迭代策略，从一系列吡唑类化合物中合成和测试小分子抑制剂，以对抗野生型RT和最常见的NNRTI耐药突变体。新出现的候选药物来西韦林（UK-453，061）以一种新的方式结合RT酶（导致独特的耐药性），抑制超过60%的携带关键RT突变的病毒，50%有效浓度（EC（50））在野生型病毒的10倍以内，对一系列人类靶标具有优异的选择性。总的来说，来西韦林是一种高效和选择性的NNRTI，对NNRTI耐药病毒具有优异的疗效。
The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC(50)s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.