Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function

Jay Chauhan, Shen En Chen, Katherine J. Fenstermacher, Aurash Naser-Tavakolian, Tali Reingewertz, Rosene Salmo, Christian Lee, Emori Williams, Mithun Raje, Eric Sundberg, Jeffrey J. Destefano, Ernesto Freire, Steven Fletcher

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Small-molecule mimetics of the β-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest Ki of 11 μM.

Original languageEnglish (US)
Pages (from-to)7095-7109
Number of pages15
JournalBioorganic and Medicinal Chemistry
Issue number21
StatePublished - Nov 1 2015


  • 1,4-Benzodiazepine
  • HIV-1 protease
  • Protein-protein interaction
  • Proteomimetic
  • β-Hairpin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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