title: Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries.
abstract: Clinically approved inhibitors of the HIV-1 protease function via a competitive mechanism. A particular vulnerability of competitive inhibitors is their sensitivity to increases in substrate concentration, as may occur during virion assembly, budding and processing into a mature infectious viral particle. Advances in chemical synthesis have led to the development of new high-diversity chemical libraries using rapid in-solution syntheses. These libraries have been shown previously to be effective at disrupting protein-protein and protein-nucleic acid interfaces. We have screened 44000 compounds from such a library to identify inhibitors of the HIV-1 protease. One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations. Moreover, analysis of this compound suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Max W
authors.initials: MW
authors.lastname: Chang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Giffin
authors.forename: Rolf
authors.initials: R
authors.lastname: Muller
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Savage
authors.forename: Ying C
authors.initials: YC
authors.lastname: Lin
authors.forename: Sukwon
authors.initials: S
authors.lastname: Hong
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Landon R
authors.initials: LR
authors.lastname: Whitby
authors.forename: John H
authors.initials: JH
authors.lastname: Elder
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
mesh_terms: D020650:Combinatorial Chemistry Techniques; D016333:HIV Protease / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1