Prajapati Dhaval G, Ramajayam R, Yadav Mange Ram, Giridhar Rajani
Pharmacy Department, Kalabhavan, The M.S. University of Baroda, Vadodara, India.
Bioorg Med Chem. 2009 Aug 15;17(16):5744-62. doi: 10.1016/j.bmc.2009.06.060. Epub 2009 Jul 3.
AIDS has become the leading pandemic disease, and is the cause of death worldwide. Presently, HAART treatment, a combination of reverse transcriptase (RT) and protease inhibitors is also unsuccessful due to the virus getting resistant to the drugs because of mutational changes. Two types of RT inhibitors exist namely nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The NNRTIs which bind to an allosteric site on RT are an important arsenal of drugs against HIV-1. The specificity of NNRTIs towards HIV-1 has led to extensive structural and molecular modelling studies of enzyme complexes and chemical synthesis of second and third-generation NNRTIs. The major drawbacks of NNRTIs are generation of resistance and pharmacokinetic problems. By mutational studies of non-nucleoside inhibitor binding pocket (NNIBP) some amino acids which were found to play an important role in proper binding resulted less prone to mutation. In this review we present a chronological history of NNRTI development, also highlighting the need for small molecules belonging to the NNRTI class for the management of AIDS.
艾滋病已成为主要的大流行性疾病，也是全球范围内的死因。目前，高效抗逆转录病毒治疗（HAART），即逆转录酶（RT）抑制剂和蛋白酶抑制剂的联合使用，也因病毒因突变而对药物产生耐药性而未取得成功。存在两种类型的RT抑制剂，即核苷类逆转录酶抑制剂（NRTIs）和非核苷类逆转录酶抑制剂（NNRTIs）。与RT上的变构位点结合的NNRTIs是对抗HIV-1的重要药物武器库。NNRTIs对HIV-1的特异性导致了对酶复合物的广泛结构和分子建模研究以及第二代和第三代NNRTIs的化学合成。NNRTIs的主要缺点是产生耐药性和药代动力学问题。通过对非核苷类抑制剂结合口袋（NNIBP）的突变研究，发现一些在正确结合中起重要作用的氨基酸不易发生突变。在本综述中，我们按时间顺序介绍了NNRTIs的发展历程，同时强调了用于艾滋病治疗的NNRTI类小分子的必要性。
