Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

ACS Med Chem Lett. 2016 Jan 19;7(3):330-4. doi: 10.1021/acsmedchemlett.5b00471. eCollection 2016 Mar 10.


The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4-7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies.

Keywords: CD4; HIV; X-ray crystallography; entry inhibitor; gp120; protein−protein interactions; structure-based drug design; thermodynamics; viral inhibition.