文献类型：期刊文献

英文题名：Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays

作者：Hu, Guoping[1];Li, Xi[1];Zhang, Xuan[2];Li, Yaozong[1];Ma, Lei[1];Yang, Liu-Meng[2];Liu, Guixia[1];Li, Weihua[1];Huang, Jin[1];Shen, Xu[3];Hu, Lihong[3];Zheng, Yong-Tang[2];Tang, Yun[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Kunming Inst Zool, Chinese Acad Sci & Yunnan, Key Lab Anim Models & Human Dis Mech, Kunming 650223, Peoples R China;[3]Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Res Ctr Modernizat Tradit Chinese Med, Shanghai 201203, Peoples R China

年份：2012

卷号：55

期号：22

起止页码：10108

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000311461500057)】；

基金：This work was supported by the Program for New Century Excellent Talents in University (Grant NCET-08-0774), the Fundamental Research Funds for the Central Universities (Grant WY1113007), the Shanghai Committee of Science and Technology (Grant 11DZ2260600), the National Natural Science Foundation of China (grants 30925040 and 81102483), and the Key Scientific and Technological Program of China (grants 2012ZX10001-006 and 2012ZX09103-101-022). The cDNA coding for HIV IN catalytic core domain (residues 50-212) including the F185K solubilizing-mutation was a gift from Prof. Robert Craigie (National Institutes of Health, Bethesda, MD). The full-length plasmid pCPNat p75 was kindly provided by Prof. Zeger Debyser (Katholieke Universiteit Leuven, Belgium).

语种：英文

摘要：This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house library of natural products and their derivatives. Among the 38 compounds selected by our strategy, 18 hits were discovered. The two most potent inhibitors showed IC50 values at 0.32 and 0.26 mu M, respectively. Three compounds were subsequently selected for anti-HIV assays, among which (E)-3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (NPD170) showed the highest antiviral activity (EC50 = 1.81 mu M). The antiviral mechanism of these compounds was further explored, and the results validated that the compounds interrupted the binding of transfected IN to endogenous LEDGF/p75. These findings could be helpful for anti-HIV drug discovery.