La Regina Giuseppe, Coluccia Antonio, Silvestri Romano
Department of Chimica e Tecnologie del Farmaco, Istituto Pasteur - Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy.
Antivir Chem Chemother. 2010 Aug 11;20(6):213-37. doi: 10.3851/IMP1607.
HIV type-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV infection. NNRTI-based HAART regimes effectively suppress viral reproduction, are not cytotoxic and show favourable pharmacokinetic properties. First-generation NNRTIs suffer the rapid selection of viral variants, hampering the binding of inhibitors into the reverse transcriptase (RT) non-nucleoside binding site (NNBS). Efforts to improve these first inhibitors led to the discovery of second-generation NNRTIs that proved to be effective against the drug-resistant mutant HIV-1 strains. The success of such agents launched a new season of NNRTI design and synthesis. This paper reviews the characteristics of second-generation NNRTIs, including etravirine, rilpivirine, RDEA-806, UK-453061, BIRL 355 BS, IDX 899, MK-4965 and HBY 097. In particular, the binding modes of these inhibitors into the NNBS of the HIV-1 RT and the most clinically relevant mutant RTs are analysed and discussed.
1型人类免疫缺陷病毒（HIV-1）非核苷类逆转录酶抑制剂（NNRTIs）是高效抗逆转录病毒疗法（HAART）治疗艾滋病/ HIV感染的关键药物。基于NNRTI的HAART方案能有效抑制病毒复制，无细胞毒性，且具有良好的药代动力学特性。第一代NNRTIs会迅速筛选出病毒变体，阻碍抑制剂与逆转录酶（RT）的非核苷结合位点（NNBS）结合。改进这些第一代抑制剂的努力促使了第二代NNRTIs的发现，事实证明第二代NNRTIs对耐药突变型HIV-1毒株有效。这类药物的成功开启了NNRTI设计与合成的新篇章。本文综述了第二代NNRTIs的特性，包括依曲韦林、利匹韦林、RDEA-806、UK-453061、BIRL 355 BS、IDX 899、MK-4965和HBY 097。特别对这些抑制剂与HIV-1 RT的NNBS以及临床上最相关的突变型RT的结合模式进行了分析和讨论。
