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 J.; Zhao J.; Yang Z.; Ma L.; Mi Z.; Wu Y.; Guo J.; Zhou J.; Li X.; Guo Y.; Peng Z.; Wei T.; Yu H.; Zhang L.; Ge M.; Cen S.

机构：[1]Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical School, Beijing, 100050, China;[2]School of Pharmacy, Shanghai Jiaotong University, Shanghai, 200040, China;[3]Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical School, Beijing, 100050, China;[4]Department of Food Science, Beijing Union University, Beijing, 100101, China;[5]Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

第一机构：Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical School, Beijing, 100050, China

通讯机构：[1]Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical School, Beijing, 100050, China

年份：2017

卷号：9

期号：5

外文期刊名：Viruses

收录：Scopus(收录号：2-s2.0-85019196587)

语种：英文

外文关键词：Alternariol 5-O-methyl ether; HIV integration; Natural product; Nuclear import; Pre-integration complex

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 α/β and importin β-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. ? 2017 by the authors. Licensee MDPI, Basel, Switzerland.