Aloperine and Its Derivatives as a New Class of HIV-1 Entry Inhibitors

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• 作者：Zhao Dang ; Lei Zhu ; Weihong Lai ; Hal Bogerd ; Kuo-Hsiung Lee ; Li Huang ; Chin-Ho Chen
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：240-244
• 全文大小：347K
• ISSN：1948-5875

文摘

A quinolizidine-type alkaloid aloperine was found to inhibit HIV-1 infection by blocking HIV-1 entry. Aloperine inhibited HIV-1 envelope-mediated cell–cell fusion at low micromolar concentrations. To further improve the antiviral potency, more than 30 aloperine derivatives with a variety of N12-substitutions were synthesized. Among them, 12d with an N-(1-butyl)-4-trifluoromethoxy-benzamide side chain showed the most potent anti-HIV-1 activity with EC₅₀ at 0.69 μM. Aloperine derivatives inhibited both X4 and R5 HIV-1 Env-mediated cell–cell fusions. In addition, both BMS-806, a compound representing a class of HIV-1 gp120-targeting small molecules in clinical trials, and resistant and sensitive HIV-1 Env-mediated cell–cell fusions were equally sensitive to aloperine derivatives. These results suggest that aloperine and its derivatives are a new class of anti-HIV-1 entry inhibitors.