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

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 (<b>4</b>–<b>7</b>) 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

Structure-Based Design and Synthesis of an HIV‑1 Entry Inhibitor Exploiting X‑ray and Thermodynamic Characterization

The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC₅₀ geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. The thermodynamic signatures indicate a binding preference for the (<i>R</i>,<i>R</i>)- over the (<i>S</i>,<i>S</i>)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4–gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors