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

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.

Automated summary

This study reports the design and synthesis of butyl chain derivatives at the 3-position of the indane ring of the lead CD4-mimetic compound BNM-III-170. Optimization efforts were guided by crystallographic and computational analysis of small-molecule ligands targeting the Phe43 cavity of gp120, leading to the discovery of more potent CD4-mimetic compounds with a novel hydrogen bonding interaction between His105 and the butyl side chain. Further optimization of this interaction shows promise for the development of even more potent CD4-mimetic compounds.