De Clercq E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Farmaco. 1999 Jan-Feb;54(1-2):26-45. doi: 10.1016/s0014-827x(98)00103-7.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than thirty structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and/or clinical development [tivirapine (TIBO R-86183), loviride (alpha-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio(pyridyl)imidazole derivative S-1153]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, preferably in combination with other anti-HIV agents, are used from the start at sufficiently high concentrations. In vitro, this procedure has been shown to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations containing NNRTIs, NRTIs and/or PIs may result in an effective viral suppression and ensuing immune recovery. However, this so-called HAART (highly active antiretroviral therapy) may also fail, and this necessitates the design of new and more effective drugs and drug cocktails.
非核苷类逆转录酶抑制剂（NNRTIs）除了核苷类逆转录酶抑制剂（NRTIs）和蛋白酶抑制剂（PIs）之外，在治疗HIV-1感染方面也占据了决定性地位。从HEPT和TIBO衍生物开始，已鉴定出三十多种结构不同的化合物类别作为NNRTIs，即对HIV-1复制具有特异性抑制作用且靶向HIV-1逆转录酶（RT）的化合物。两种NNRTIs（奈韦拉平和地拉韦定）已正式获得临床使用许可，其他几种（或曾经）处于临床前和/或临床开发阶段[替韦拉平（TIBO R-86183）、洛维瑞德（α-APA R89439）、硫代羧酰苯胺UC-781、HEPT衍生物MKC-442、喹喔啉HBY 097、DMP 266（依非韦伦）、PETT衍生物（曲韦定、PETT-4、PETT-5）以及二氯苯基硫代（吡啶基）咪唑衍生物S-1153]。NNRTIs与HIV-1 RT的一个特定“口袋”位点相互作用，该位点与NRTI结合位点紧密相关但又不同。NNRTIs因NNRTI结合位点周围氨基酸的突变而迅速引发耐药性而声名狼藉。然而，如果从一开始就以足够高的浓度使用NNRTIs，最好与其他抗HIV药物联合使用，就可以避免耐药HIV毒株的出现。在体外，该方法已被证明能“消除”病毒复制并防止耐药性产生。在体内，各种包含NNRTIs、NRTIs和/或PIs的三联药物组合可能会有效抑制病毒并随后实现免疫恢复。然而，这种所谓的高效抗逆转录病毒疗法（HAART）也可能失败，这就需要设计新的、更有效的药物和药物组合。
