Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, USA.
J Med Chem. 2012 May 10;55(9):4382-96. doi: 10.1021/jm300265j. Epub 2012 Apr 23.
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-gp120 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-gp120 protein-protein interaction.
HIV-1 通过细胞感染是由病毒包膜糖蛋白 gp120 与细胞受体蛋白 CD4 之间的结合事件引发的。CD4-gp120 界面主要由两个热点区域控制：由 Phe43(CD4) 封顶的疏水性 gp120 腔和残基 Arg59(CD4) 和 Asp368(gp120) 之间的静电相互作用。CD4 模拟小分子 NBD-556(1) 结合在 gp120 腔内；然而，1 和相关的同系物显示出有限的病毒中和广度。本文报道了与同时结合两个结合热点的小分子复合的 gp120 的设计、合成、表征和 X 射线结构。这些化合物特异性地抑制 42 个 2 级 B 和 C 谱系病毒的病毒感染，并且被证明是进入 CD4-阴性细胞的拮抗剂。因此，双热点设计既提供了增强 HIV-1 进入抑制剂中和效力的手段，又为抑制 CD4-gp120 蛋白-蛋白相互作用提供了新的结构范例。
