Sarafianos Stefan G, Marchand Bruno, Das Kalyan, Himmel Daniel M, Parniak Michael A, Hughes Stephen H, Arnold Eddy
Christopher Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, MO 65211, USA.
J Mol Biol. 2009 Jan 23;385(3):693-713. doi: 10.1016/j.jmb.2008.10.071. Epub 2008 Nov 3.
The rapid replication of HIV-1 and the errors made during viral replication cause the virus to evolve rapidly in patients, making the problems of vaccine development and drug therapy particularly challenging. In the absence of an effective vaccine, drugs are the only useful treatment. Anti-HIV drugs work; so far drug therapy has saved more than three million years of life. Unfortunately, HIV-1 develops resistance to all of the available drugs. Although a number of useful anti-HIV drugs have been approved for use in patients, the problems associated with drug toxicity and the development of resistance means that the search for new drugs is an ongoing process. The three viral enzymes, reverse transcriptase (RT), integrase (IN), and protease (PR) are all good drug targets. Two distinct types of RT inhibitors, both of which block the polymerase activity of RT, have been approved to treat HIV-1 infections, nucleoside analogs (NRTIs) and nonnucleosides (NNRTIs), and there are promising leads for compounds that either block the RNase H activity or block the polymerase in other ways. A better understanding of the structure and function(s) of RT and of the mechanism(s) of inhibition can be used to generate better drugs; in particular, drugs that are effective against the current drug-resistant strains of HIV-1.
HIV-1的快速复制以及病毒复制过程中出现的错误，导致该病毒在患者体内迅速进化，这使得疫苗研发和药物治疗面临极大挑战。在缺乏有效疫苗的情况下，药物是唯一有效的治疗手段。抗HIV药物确实有效；迄今为止，药物治疗已挽救了超过300万人年的生命。不幸的是，HIV-1会对所有可用药物产生耐药性。尽管已有多种有效的抗HIV药物获批用于患者治疗，但药物毒性和耐药性问题意味着新药研发仍是一个持续的过程。三种病毒酶，即逆转录酶（RT）、整合酶（IN）和蛋白酶（PR）都是很好的药物靶点。两种不同类型的RT抑制剂已获批用于治疗HIV-1感染，它们均可阻断RT的聚合酶活性，即核苷类似物（NRTIs）和非核苷类药物（NNRTIs），而且对于能够阻断RNase H活性或以其他方式阻断聚合酶的化合物，也有一些很有前景的研究线索。深入了解RT的结构和功能以及抑制机制，有助于研发出更好的药物；特别是针对当前HIV-1耐药毒株有效的药物。
