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

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 3rd

doi:10.1021/acsmedchemlett.1c00437

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

ACS Med Chem Lett. 2021 Oct 29;12(11):1824-1831. doi: 10.1021/acsmedchemlett.1c00437. eCollection 2021 Nov 11.

Authors

Affiliations

¹ Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
² Department of Biochemistry and Molecular Biophysics and Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, United States.
³ Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States.
⁴ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, United States.
⁵ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, United States.

Abstract

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.

Abstract

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