Structure-based design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization

Judith M. LaLonde, Matthew Le-Khac, David M. Jones, Joel R. Courter, Jongwoo Park, Arne Schön, Amy M. Princiotto, Xueling Wu, John R. Mascola, Ernesto Freire, Joseph Sodroski, Navid Madani, Wayne A. Hendrickson, Amos B. Smith

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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 (R,R)- over the (S,S)-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.

Original languageEnglish (US)
Pages (from-to)338-343
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number3
StatePublished - Mar 14 2013


  • 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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