2. Academic Validation
  3. 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

  • ACS Med Chem Lett. 2021 Oct 29;12(11):1824-1831. doi: 10.1021/acsmedchemlett.1c00437.
Christopher J Fritschi 1,  Shuaiyi Liang 2,  Mohammadjavad Mohammadi 3,  Saumya Anang 4,  Francesca Moraca 3,  Junhua Chen 1,  Navid Madani 4,  Joseph G Sodroski 4 4 5,  Cameron F Abrams 3,  Wayne A Hendrickson 2 2,  Amos B Smith 3rd 1
Affiliations

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.
PMID: 34795873 DOI: 10.1021/acsmedchemlett.1c00437
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.

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