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 I Freire, Steven Fletcher

Research output: Contribution to journalArticle

Abstract

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
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2015

Fingerprint

Flaps
Scaffolds
Catalytic Domain
Molecules
Enzymes
Access control
Proteins
Peptide Hydrolases
Kinetics
HIV-1
Binding Sites
HIV
Human immunodeficiency virus 1 p16 protease
Bz-423

Keywords

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

ASJC Scopus subject areas

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

Cite this

Chauhan, J., Chen, S. E., Fenstermacher, K. J., Naser-Tavakolian, A., Reingewertz, T., Salmo, R., ... Fletcher, S. (2015). Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function. Bioorganic and Medicinal Chemistry, 23(21), 7095-7109. https://doi.org/10.1016/j.bmc.2015.09.002

Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function. / Chauhan, Jay; Chen, Shen En; Fenstermacher, Katherine J.; Naser-Tavakolian, Aurash; Reingewertz, Tali; Salmo, Rosene; Lee, Christian; Williams, Emori; Raje, Mithun; Sundberg, Eric; Destefano, Jeffrey J.; Freire, Ernesto I; Fletcher, Steven.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 21, 01.11.2015, p. 7095-7109.

Research output: Contribution to journalArticle

Chauhan, J, Chen, SE, Fenstermacher, KJ, Naser-Tavakolian, A, Reingewertz, T, Salmo, R, Lee, C, Williams, E, Raje, M, Sundberg, E, Destefano, JJ, Freire, EI & Fletcher, S 2015, 'Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function', Bioorganic and Medicinal Chemistry, vol. 23, no. 21, pp. 7095-7109. https://doi.org/10.1016/j.bmc.2015.09.002
Chauhan J, Chen SE, Fenstermacher KJ, Naser-Tavakolian A, Reingewertz T, Salmo R et al. Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function. Bioorganic and Medicinal Chemistry. 2015 Nov 1;23(21):7095-7109. https://doi.org/10.1016/j.bmc.2015.09.002
Chauhan, Jay ; Chen, Shen En ; Fenstermacher, Katherine J. ; Naser-Tavakolian, Aurash ; Reingewertz, Tali ; Salmo, Rosene ; Lee, Christian ; Williams, Emori ; Raje, Mithun ; Sundberg, Eric ; Destefano, Jeffrey J. ; Freire, Ernesto I ; Fletcher, Steven. / Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 21. pp. 7095-7109.
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