title: Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV.
abstract: 3C-like (3CL) protease is essential for the life cycle of severe acute respiratory syndrome-coronavirus (SARS-CoV) and therefore represents a key anti-viral target. A compound library consisting of 960 commercially available drugs and biologically active substances was screened for inhibition of SARS-CoV 3CL protease. Potent inhibition was achieved using the mercury-containing compounds thimerosal and phenylmercuric acetate, as well as hexachlorophene. As well, 1-10 microM of each compound inhibited viral replication in Vero E6 cell culture. Detailed mechanism studies using a fluorescence-based protease assay demonstrated that the three compounds acted as competitive inhibitors (Ki=0.7, 2.4, and 13.7 microM for phenylmercuric acetate, thimerosal, and hexachlorophene, respectively). A panel of metal ions including Zn2+ and its conjugates were then evaluated for their anti-3CL protease activities. Inhibition was more pronounced using a zinc-conjugated compound (1-hydroxypyridine-2-thione zinc; Ki=0.17 microM) than using the ion alone (Ki=1.1 microM).
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, National Defense Medical Center, Taipei 115, Taiwan, ROC.
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Chih-Jung
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Yeau-Ching
authors.initials: YC
authors.lastname: Wang
authors.forename: Kuo-Kuei
authors.initials: KK
authors.lastname: Huang
authors.forename: Coney P-C
authors.initials: CP
authors.lastname: Lin
authors.forename: Ping-Fang
authors.initials: PF
authors.lastname: Huang
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Liang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002522:Chlorocebus aethiops; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D008670:Metals / Q000737:chemistry*; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: D008670:Metals; D011480:Protease Inhibitors; D014764:Viral Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases