Identification of gp120 Residue His105 as a Novel Target for HIV-1 Neutralization by Small-Molecule CD4-Mimics
Identification of gp120 Residue His105 as a Novel Target for HIV-1 Neutralization by Small-Molecule CD4-Mimics
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gp120残基His105作为小分子CD4-Mimics中和HIV-1的新靶点的鉴定
DOI：
10.1021/acsmedchemlett.1c00437
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发表时间：
2021-10-29
影响因子：
4.2
通讯作者：
Smith, Amos B., III
中科院分区：
文献类型：
--
作者：
Fritschi, Christopher J.;Liang, Shuaiyi;Smith, Amos B., III
本文报道了抑制人类免疫缺陷病毒（HIV-1）感染的CD_4模拟物BNM-Ⅲ-170的茚满环3位丁基链衍生物的设计与合成。优化工作是由包膜糖蛋白gp 120的Phe 43腔的小分子配体的晶体学和计算分析指导的。11-21的生物学评价显示，与BNM-III-170相比，该系列CD 4模拟化合物的成员能够更有效地抑制HIV-1病毒进入靶细胞，且范围更广。14，16和17的结合口袋的晶体学分析揭示了His 105和丁基侧链上的伯羟基之间的新型氢键相互作用。进一步优化这种与His 105残基的相互作用有望获得更有效的CD 4模拟化合物。
The design and synthesis of butyl chain derivatives at the indane ring 3-position of our lead CD4-mimetic compound BNM-III-170 that inhibits human immunodeficiency virus (HIV-1) infection are reported. Optimization efforts were guided by crystallographic and computational analysis of the small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120. Biological evaluation of 11-21 revealed that members of this series of CD4-mimetic compounds are able to inhibit HIV-1 viral entry into target cells more potently and with greater breadth compared to BNM-III-170. Crystallographic analysis of the binding pocket of 14, 16, and 17 revealed a novel hydrogen bonding interaction between His105 and a primary hydroxyl group on the butyl side chain. Further optimization of this interaction with the His105 residue holds the promise of more potent CD4-mimetic compounds.