title: A Novel Class of HIV-1 Antiviral Agents Targeting HIV via a SUMOylation-Dependent Mechanism.
abstract: We have recently identified a chemotype of small ubiquitin-like modifier (SUMO)-specific protease (SENP) inhibitors. Prior to the discovery of their SENP inhibitory activity, these compounds were found to inhibit HIV replication, but with an unknown mechanism. In this study, we investigated the mechanism of how these compounds inhibit HIV-1. We found that they do not affect HIV-1 viral production, but significantly inhibited the infectivity of the virus. Interestingly, virions produced from cells treated with these compounds could gain entry and carry out reverse transcription, but could not efficiently integrate into the host genome. This phenotype is different from the virus produced from cells treated with the class of anti-HIV-1 agents that inhibit HIV protease. Upon removal of the SUMO modification sites in the HIV-1 integrase, the compound no longer alters viral infectivity, indicating that the effect is related to SUMOylation of the HIV integrase. This study identifies a novel mechanism for inhibiting HIV-1 integration and a new class of small molecules that inhibits HIV-1 via such mechanism that may contribute a new strategy for cure of HIV-1 by inhibiting the production of infectious virions upon activation from latency.
authors.affiliation: Department of Molecular Medicine, 1500 East Duarte Road, CA 91010.
authors.forename: Ikenna G
authors.initials: IG
authors.lastname: Madu
authors.affiliation: Department of Virology, 1500 East Duarte Road, CA 91010.
authors.forename: Shirley
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular Medicine, 1500 East Duarte Road, CA 91010.
authors.forename: Baozong
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010.
authors.forename: Haitang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Virology, 1500 East Duarte Road, CA 91010.
authors.forename: Tammy
authors.initials: T
authors.lastname: Chang
authors.affiliation: Department of Molecular Medicine, 1500 East Duarte Road, CA 91010.
authors.forename: Yi-Jia
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Molecular Medicine, 1500 East Duarte Road, CA 91010.
authors.forename: Ramir
authors.initials: R
authors.lastname: Vega
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010.
authors.forename: John
authors.initials: J
authors.lastname: Rossi
authors.affiliation: Department of Virology, 1500 East Duarte Road, CA 91010.
authors.forename: Jiing-Kuan
authors.initials: JK
authors.lastname: Yee
authors.affiliation: Department of Virology, 1500 East Duarte Road, CA 91010.
authors.forename: John
authors.initials: J
authors.lastname: Zaia
authors.affiliation: Department of Molecular Medicine, 1500 East Duarte Road, CA 91010.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D058207:Sumoylation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase