Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States.
J Med Chem. 2013 Apr 11;56(7):2738-46. doi: 10.1021/jm301271j. Epub 2013 Feb 20.
HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs.
HIV-1 逆转录酶（RT）在病毒复制过程中经历一系列构象变化，是抗逆转录病毒治疗的核心靶点。RT 的固有灵活性可以为抑制作用提供新的变构结合部位。能够衍射至 2Å 分辨率以上的 RT 晶体促进了使用 X 射线晶体学的片段筛选技术对 RT 进行新的可成药部位的探测。共筛选出 775 个片段，将其分成 143 个鸡尾酒混合物，将其浸泡在与非核苷类药物利匹韦林（TMC278）形成复合物的 RT 晶体中。发现了 7 个新的结合部位，包括 IN 核苷酸结合部位、指节区、NNRTI 相邻部位和 399 部位，位于 RT 的聚合酶区域，以及 428、RNase H 引物结合区相邻部位和 507 部位，位于 RNase H 区域。其中 3 个部位（指节区、NNRTI 相邻部位和 IN 核苷酸结合部位）具有抑制作用，为发现新的抗艾滋病药物提供了机会。
