文献类型：期刊文献

英文题名：Microbial Natural Product Alternariol 5-O-Methyl Ether Inhibits HIV-1 Integration by Blocking Nuclear Import of the Pre-Integration Complex

作者：Ding, Jiwei[1,2];Zhao, Jianyuan[1,2];Yang, Zhijun[3];Ma, Ling[1,2];Mi, Zeyun[1,2];Wu, Yanbing[1,2];Guo, Jiamei[2,4];Zhou, Jinmin[1,2];Li, Xiaoyu[1,2];Guo, Ying[2,4];Peng, Zonggen[1,2];Wei, Tao[5];Yu, Haisheng[6];Zhang, Liguo[6];Ge, Mei[3];Cen, Shan[1,2]

第一作者：Ding, Jiwei

通讯作者：Cen, S[1];Cen, S[2]

机构：[1]Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China;[2]Peking Union Med Sch, Beijing 100050, Peoples R China;[3]Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200040, Peoples R China;[4]Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China;[5]Beijing Union Univ, Dept Food Sci, Beijing 100101, Peoples R China;[6]Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China

第一机构：Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China

通讯机构：[1]corresponding author), Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China;[2]corresponding author), Peking Union Med Sch, Beijing 100050, Peoples R China.

年份：2017

卷号：9

期号：5

外文期刊名：VIRUSES-BASEL

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000404226000013)】；

基金：This work was supported in part by 973 program (2012CB911102 CS), National Mega-project for Innovative Drugs (2012ZX09301002-001-015 and 2012ZX09301002-005-002), National Mega-Project for Infectious Disease (2013ZX10004601-002), and the Xiehe Scholar (S.C.). We thank the National Infrastructure of Microbial Resources (NIMR-2014-3) for providing valuable reagents.

语种：英文

外文关键词：HIV integration; pre-integration complex; alternariol 5-O-methyl ether; nuclear import; natural product

摘要：While Highly Active Antiretroviral Therapy (HAART) has significantly decreased the mortality of human immunodeficiency virus (HIV)-infected patients, emerging drug resistance to approved HIV-1 integrase inhibitors highlights the need to develop new antivirals with novel mechanisms of action. In this study, we screened a library of microbial natural compounds from endophytic fungus Colletotrichum sp. and identified alternariol 5-O-methyl ether (AME) as a compound that inhibits HIV-1 pre-integration steps. Time-of addition analysis, quantitative real-time PCR, confocal microscopy, and WT viral replication assay were used to elucidate the mechanism. As opposed to the approved integrase inhibitor Raltegravir, AME reduced both the integrated viral DNA and the 2-long terminal repeat (2-LTR) circular DNA, which suggests that AME impairs the nuclear import of viral DNA. Further confocal microscopy studies showed that AME specifically blocks the nuclear import of HIV-1 integrase and pre-integration complex without any adverse effects on the importin alpha/beta and importin beta-mediated nuclear import pathway in general. Importantly, AME inhibited Raltegravir-resistant HIV-1 strains and exhibited a broad anti-HIV-1 activity in diverse cell lines. These data collectively demonstrate the potential of AME for further development into a new HIV inhibitor, and suggest the utility of viral DNA nuclear import as a target for anti-HIV drug discovery.