Du Zhihua, Lind Kenneth E, James Thomas L
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Franciso, CA 94143, USA.
Chem Biol. 2002 Jun;9(6):707-12. doi: 10.1016/s1074-5521(02)00151-5.
HIV-1 TAR RNA functions critically in viral replication by binding the transactivating regulatory protein Tat. We recently identified several compounds that experimentally inhibit the Tat-TAR interaction completely at a 100 nM concentration. We used computational screening of the 181,000-compound Available Chemicals Directory against the three-dimensional structure of TAR [1]. Here we report the NMR-derived structure of TAR complexed with acetylpromazine. This structure represents a new class of compounds with good bioavailability and low toxicity that bind with high affinity to TAR. NMR data unambiguously show that acetylpromazine binds only to the unique 5' bulge site to which the Tat protein binds. Specificity and affinity of binding are conferred primarily by a network of base stacking and hydrophobic interactions. Acetylpromazine alters the structure of free TAR less than Tat peptides and neomycin do.
HIV-1反式激活应答元件（TAR）RNA通过与反式激活调节蛋白Tat结合，在病毒复制中发挥关键作用。我们最近鉴定出几种化合物，它们在100 nM浓度下可完全实验性抑制Tat-TAR相互作用。我们利用181,000种化合物的可用化学品目录针对TAR的三维结构进行了计算筛选[1]。在此，我们报告与乙酰丙嗪复合的TAR的核磁共振（NMR）衍生结构。该结构代表了一类具有良好生物利用度和低毒性的新型化合物，它们以高亲和力与TAR结合。NMR数据明确显示，乙酰丙嗪仅与Tat蛋白结合的独特5'凸起位点结合。结合的特异性和亲和力主要由碱基堆积和疏水相互作用网络赋予。乙酰丙嗪对游离TAR结构的改变小于Tat肽和新霉素。
