title: A modular approach to HIV-1 proteinase inhibitor design.
abstract: HIV-1 proteinase represents a promising target for antiviral chemotherapy. We have designed, synthesized, and tested modular inhibitors combining an active-site inhibitor tethered to a structure targeted to the dimerization domain of the enzyme. At pH 5 the parent active site inhibitor, the equimolar mixture of active site and dimerization inhibitors, and the best compound from our series of modular inhibitors show the same inhibition activity. At neutral pH, however, the combination of the dimerization and active-site inhibitors shows a synergistic effect. Moreover, the modular inhibitor has an IC50 value 5x lower than the parent active site inhibitor and 2x lower than the equimolar mixture of the two parent inhibitors. The Lineweaver-Burk plot for modular inhibitors corresponds to a pattern for mixed type inhibition.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic. uhlikova@prfdec.natur.cuni.cz
authors.forename: T
authors.initials: T
authors.lastname: Uhlíková
authors.forename: J
authors.initials: J
authors.lastname: Konvalinka
authors.forename: I
authors.initials: I
authors.lastname: Pichová
authors.forename: M
authors.initials: M
authors.lastname: Soucek
authors.forename: H G
authors.initials: HG
authors.lastname: Kräusslich
authors.forename: J
authors.initials: J
authors.lastname: Vondrásek
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D010455:Peptides; D016333:HIV Protease