title: Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function.
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 K(i) of 11 μM.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Chauhan
authors.affiliation: Department of Biology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
authors.forename: Shen-En
authors.initials: SE
authors.lastname: Chen
authors.affiliation: Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Fenstermacher
authors.affiliation: Department of Biology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
authors.forename: Aurash
authors.initials: A
authors.lastname: Naser-Tavakolian
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 725 West Lombard St., Baltimore, MD 21201, USA.
authors.forename: Tali
authors.initials: T
authors.lastname: Reingewertz
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Rosene
authors.initials: R
authors.lastname: Salmo
authors.affiliation: PharmD Program, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Lee
authors.affiliation: Vivien T Thomas Medical Arts Academy, 100 N Calhoun St., Baltimore, MD 21223, USA.
authors.forename: Emori
authors.initials: E
authors.lastname: Williams
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Mithun
authors.initials: M
authors.lastname: Raje
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 725 West Lombard St., Baltimore, MD 21201, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sundberg
authors.affiliation: Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: DeStefano
authors.affiliation: Department of Biology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D001569:Benzodiazepines; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: 1,4-Benzodiazepine; HIV-1 protease; HIV/AIDS; Protein–protein interaction; Proteomimetic; β-Hairpin