Identification of gp120 Residue His105 as a Novel Target for HIV-1 Neutralization by Small-Molecule CD4-Mimics

作者：Christopher Fritschi, Shuaiyi Liang, Mohammadjavad Mohammadi, Saumya Anang, Francesca Moraca, Junhua Chen, Navid Madani, Joseph Sodroski, Cameron F. Abrams, Wayne A. Hendrickson, Amos B. Smith · 发表于：ACS Medicinal Chemistry Letters · 年份：2021 · DOI：10.1021/acsmedchemlett.1c00437 · 被引用次数：8 · 研究领域：HIV Research and Treatment、HIV/AIDS drug development and treatment、RNA and protein synthesis mechanisms

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.