Characterization of New Cationic N,N-Dimethyl[70]fulleropyrrolidinium Iodide Derivatives as Potent HIV-1 Maturation Inhibitors

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• 作者：Edison CastroZachary S. Martinez ; Chang-Soo Seong ; Andrea Cabrera-EspinozaMauro Ruiz ; Andrea Hernandez Garcia ; Federico Valdez ; Manuel Llano ; Luis Echegoyen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：10963-10973
• 全文大小：572K
• ISSN：1520-4804

文摘

HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% of HIV-1 infectivity at low micromolar concentrations. Analysis of the HIV-1 life cycle indicated that these compounds inhibit viral maturation by impairing Gag and Gag-Pol processing. Importantly, fullerene derivatives 2a–c did not inhibit in vitro PR activity and strongly interacted with HIV immature capsid protein in pull-down experiments. Furthermore, these compounds potently blocked infectivity of viruses harboring mutant PR that are resistant to multiple PR inhibitors or mutant Gag proteins that confer resistance to the maturation inhibitor Bevirimat. Collectively, our studies indicate fullerene derivatives 2a–c as potent and novel HIV-1 maturation inhibitors.