Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity

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• 作者：Francesca Curreli ; Young Do Kwon ; Hongtao Zhang ; Daniel Scacalossi ; Dmitry S. Belov ; Artur A. Tikhonov ; Ivan A. Andreev ; Andrea Altieri ; Alexander V. Kurkin ; Peter D. Kwong ; Asim K. Debnath
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：6909-6927
• 全文大小：778K
• ISSN：1520-4804

文摘

Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC₅₀ as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.