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

Bruno Melillo, Shuaiyi Liang, Jongwoo Park, Arne Schön, Joel R. Courter, Judith M. Lalonde, Daniel J. Wendler, Amy M. Princiotto, Michael S. Seaman, Ernesto Freire, Joseph Sodroski, Navid Madani, Wayne A. Hendrickson, Amos B. Smith

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)330-334
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number3
StatePublished - Mar 10 2016


  • CD4
  • HIV
  • X-ray crystallography
  • entry inhibitor
  • gp120
  • protein-protein interactions
  • structure-based drug design
  • thermodynamics
  • viral inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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