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Synthetic, structural mimetics of the ß-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; Fletcher, Steven.
Afiliación
  • Chauhan J; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
  • Chen SE; Department of Biology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
  • Fenstermacher KJ; Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
  • Naser-Tavakolian A; Department of Biology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
  • Reingewertz T; Department of Microbiology and Immunology, University of Maryland School of Medicine, 725 West Lombard St., Baltimore, MD 21201, USA.
  • Salmo R; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
  • Lee C; PharmD Program, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
  • Williams E; Vivien T Thomas Medical Arts Academy, 100 N Calhoun St., Baltimore, MD 21223, USA.
  • Raje M; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
  • Sundberg E; Department of Microbiology and Immunology, University of Maryland School of Medicine, 725 West Lombard St., Baltimore, MD 21201, USA.
  • DeStefano JJ; Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
  • Freire E; Department of Biology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
  • Fletcher S; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA. Electronic address: sfletcher@rx.umaryland.edu.
Bioorg Med Chem ; 23(21): 7095-109, 2015 Nov 01.
Article en En | MEDLINE | ID: mdl-26474665
ABSTRACT
Small-molecule mimetics of the ß-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 K(i) of 11 µM.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteasa del VIH / Inhibidores de la Proteasa del VIH / Bibliotecas de Moléculas Pequeñas Límite: Humans Idioma: En Año: 2015 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteasa del VIH / Inhibidores de la Proteasa del VIH / Bibliotecas de Moléculas Pequeñas Límite: Humans Idioma: En Año: 2015 Tipo del documento: Article