Singh Kamalendra, Marchand Bruno, Kirby Karen A, Michailidis Eleftherios, Sarafianos Stefan G
Christopher Bond Life Sciences Center & Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, Missouri 65211, USA;
Viruses. 2010 Feb 11;2(2):606-638. doi: 10.3390/v2020606.
HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components of Highly Active Anti-Retroviral Therapies (HAART). It remains the target of extensive structural studies that continue unabated for almost twenty years. The crystal structures of wild-type or drug-resistant mutant HIV RTs in the unliganded form or in complex with substrates and/or drugs have offered valuable glimpses into the enzyme's folding and its interactions with DNA and dNTP substrates, as well as with nucleos(t)ide reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTIs) drugs. These studies have been used to interpret a large body of biochemical results and have paved the way for innovative biochemical experiments designed to elucidate the mechanisms of catalysis and drug inhibition of polymerase and RNase H functions of RT. In turn, the combined use of structural biology and biochemical approaches has led to the discovery of novel mechanisms of drug resistance and has contributed to the design of new drugs with improved potency and ability to suppress multi-drug resistant strains.
HIV-1逆转录酶（HIV-1 RT）一直是众多已获批抗艾滋病药物的作用靶点，这些药物是高效抗逆转录病毒疗法（HAART）的关键组成部分。它仍然是广泛结构研究的对象，这种研究持续了近二十年且热度不减。野生型或耐药突变型HIV RT在无配体形式下或与底物和/或药物形成复合物时的晶体结构，为了解该酶的折叠情况及其与DNA和dNTP底物以及与核苷（酸）逆转录酶抑制剂（NRTI）和非核苷逆转录酶抑制剂（NNRTI）药物的相互作用提供了有价值的线索。这些研究已被用于解释大量的生化结果，并为旨在阐明RT聚合酶和RNase H功能的催化和药物抑制机制的创新性生化实验铺平了道路。反过来，结构生物学和生化方法的联合使用导致了耐药新机制的发现，并有助于设计出效力更强、能够抑制多药耐药菌株的新药。
