Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity.
Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity.
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DOI：
10.1021/acs.jmedchem.5b00709
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发表时间：
2015-09-10
影响因子：
7.3
通讯作者：
Debnath AK
中科院分区：
文献类型：
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作者：
Curreli F;Kwon YD;Zhang H;Scacalossi D;Belov DS;Tikhonov AA;Andreev IA;Altieri A;Kurkin AV;Kwong PD;Debnath AK
之前我们报道了NBD-556及其类似物的发现和设计，证明了它们作为HIV-1进入抑制剂的潜力。然而，开发这些抑制剂的进展一直受到其cd4激动剂特性的阻碍，这是作为药物使用的不利特性。在这里，我们证明了一个完整的cd4激动剂（NBD-556）通过一个部分的cd4激动剂（NBD-09027），成功转化为一个完整的cd4拮抗剂（NBD-11021），通过基于结构的修饰关键草酰胺中间区域，以前认为是不耐受修饰。NBD-11021对这类抑制剂表现出前所未有的中和作用，对56种代表不同临床分离亚型的Env-pseudotyped HIV-1具有泛中和作用（IC50低至270 nM）。NBD-11021与单个HIV-1 gp120核的共晶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框架。
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.