title: Screening of drugs by FRET analysis identifies inhibitors of SARS-CoV 3CL protease.
abstract: SARS-CoV 3CL protease is essential for viral protein processing and is regarded as a good drug target to prevent SARS-CoV replication. In the present study, we established a high-throughput FRET technique for screening for anti-SARS-CoV 3CL protease drugs. Of a thousand existing drugs examined, hexachlorophene was identified as the most potent in inhibiting SARS-CoV 3CL protease. Further characterization showed that it was effective at micromolar concentrations (K(i) = 4 microM). The binding mode was competitive, and the inhibitory effect was dependent on preincubation time. Two other drugs, triclosan and nelfinavir, were about 10 times less potent. The structure-based search and biological evaluation of various hexachlorophene analogues were described. These analogues gave optimal inhibitory activity against SARS-CoV 3CL protease with IC(50) values ranging from 7.6 to 84.5 microM. Optimization of hexachlorophene analogues was shown to provide several active 3CL protease inhibitors that function as potential anti-SARS agents.
authors.affiliation: Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.forename: Vicky
authors.initials: V
authors.lastname: Huang
authors.forename: Ti-Chun
authors.initials: TC
authors.lastname: Chao
authors.forename: Chwan-Deng
authors.initials: CD
authors.lastname: Hsiao
authors.forename: Atsui
authors.initials: A
authors.lastname: Lin
authors.forename: Ming-Fu
authors.initials: MF
authors.lastname: Chang
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Chow
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D010450:Endopeptidases / Q000032:analysis; D004789:Enzyme Activation; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods*; D007700:Kinetics; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000032:analysis / Q000737:chemistry*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D014764:Viral Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D011480:Protease Inhibitors; D014764:Viral Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases