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Viruses 2017, 9(5), 105; doi:10.3390/v9050105

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

1
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and 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 and 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
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Andrew Mehle
Received: 28 February 2017 / Revised: 19 April 2017 / Accepted: 5 May 2017 / Published: 10 May 2017
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Abstract

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. View Full-Text
Keywords: HIV integration; pre-integration complex; alternariol 5-O-methyl ether; nuclear import; natural product HIV integration; pre-integration complex; alternariol 5-O-methyl ether; nuclear import; natural product
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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. Microbial Natural Product Alternariol 5-O-Methyl Ether Inhibits HIV-1 Integration by Blocking Nuclear Import of the Pre-Integration Complex. Viruses 2017, 9, 105.

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