鉴定gp120残基His105作为小分子CD4模拟物对HIV-1中和作用的新靶点。
Identification of gp120 Residue His105 as a Novel Target for HIV-1 Neutralization by Small-Molecule CD4-Mimics.
作者信息
Fritschi Christopher J, Liang Shuaiyi, Mohammadi Mohammadjavad, Anang Saumya, Moraca Francesca, Chen Junhua, Madani Navid, Sodroski Joseph G, Abrams Cameron F, Hendrickson Wayne A, Smith Amos B
机构信息
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Department of Biochemistry and Molecular Biophysics and Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, United States.
出版信息
ACS Med Chem Lett. 2021 Oct 29;12(11):1824-1831. doi: 10.1021/acsmedchemlett.1c00437. eCollection 2021 Nov 11.
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 - 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 , , and 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.
报道了在我们的先导CD4模拟化合物BNM-III-170的茚满环3位上设计和合成丁基链衍生物，该化合物可抑制人类免疫缺陷病毒（HIV-1）感染。优化工作以包膜糖蛋白gp120的Phe43腔小分子配体的晶体学和计算分析为指导。对该系列CD4模拟化合物的生物学评估表明，与BNM-III-170相比，该系列化合物能够更有效且更广泛地抑制HIV-1病毒进入靶细胞。对[具体化合物名称1]、[具体化合物名称2]和[具体化合物名称3]结合口袋的晶体学分析揭示了His105与丁基侧链上的伯羟基之间存在新型氢键相互作用。与His105残基进一步优化这种相互作用有望得到更有效的CD4模拟化合物。
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