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
  • 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.

Products