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具有广谱抗HIV-1活性的小分子CD4拮抗剂的基于结构的设计

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

作者信息

Curreli Francesca, Kwon Young Do, Zhang Hongtao, Scacalossi Daniel, Belov Dmitry S, Tikhonov Artur A, Andreev Ivan A, Altieri Andrea, Kurkin Alexander V, Kwong Peter D, Debnath Asim K

机构信息

Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, New York 10065, United States.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.

出版信息

J Med Chem. 2015 Sep 10;58(17):6909-6927. doi: 10.1021/acs.jmedchem.5b00709. Epub 2015 Aug 28.

Abstract

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.

摘要

我们之前报道了NBD - 556及其类似物的发现与设计,这些化合物显示出作为HIV - 1进入抑制剂的潜力。然而,这些抑制剂的开发进展因它们具有CD4激动剂特性而受阻,这是作为药物使用时的一个不利特征。在此,我们通过对关键的草酰胺中间区域进行基于结构的修饰,成功地将一个完全的CD4激动剂(NBD - 556),经过一个部分CD4激动剂(NBD - 09027),转化为一个完全的CD4拮抗剂(NBD - 11021),而该关键区域之前被认为不耐受修饰。对于这类抑制剂,NBD - 11021表现出前所未有的中和广度,对一组代表临床分离株不同亚型的56种Env假型HIV - 1具有泛中和作用(IC50低至270 nM)。NBD - 11021与单体HIV - 1 gp120核心形成的共晶体结构揭示了其详细的结合特征。该研究有望为进一步开发NBD系列作为HIV - 1进入抑制剂用于临床治疗艾滋病提供一个框架。

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