Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors

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• 作者：Judith M. LaLonde ; Young Do Kwon ; David M. Jones ; Alexander W. Sun ; Joel R. Courter ; Takahiro Soeta ; Toyoharu Kobayashi ; Amy M. Princiotto ; Xueling Wu ; Arne Sch枚n ; Ernesto Freire ; Peter D. Kwong ; John R. Mascola ; Joseph Sodroski ; Navid Madani ; Amos B. Smith ; III
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4382-4396
• 全文大小：715K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4鈥揼p120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43_CD4 and an electrostatic interaction between residues Arg59_CD4 and Asp368_gp120. The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection of 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4-negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4鈥揼p120 protein鈥損rotein interaction.