Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV.
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).
Hsu
John T-A
JT
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, National Defense Medical Center, Taipei 115, Taiwan, ROC.
Kuo
Chih-Jung
CJ
Hsieh
Hsing-Pang
HP
Wang
Yeau-Ching
YC
Huang
Kuo-Kuei
KK
Lin
Coney P-C
CP
Huang
Ping-Fang
PF
Chen
Xin
X
Liang
Po-Huang
PH
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*
D008670:Metals; D011480:Protease Inhibitors; D014764:Viral Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases