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

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journal contribution
posted on 2021-10-29, 20:03 authored by Christopher J. Fritschi, Shuaiyi Liang, Mohammadjavad Mohammadi, Saumya Anang, Francesca Moraca, Junhua Chen, Navid Madani, Joseph G. Sodroski, Cameron F. Abrams, Wayne A. Hendrickson, Amos B. Smith
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 1121 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.