Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics.
The severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infected more than 8,000 people across 29 countries and caused more than 900 fatalities. Based on the concept of chemical genetics, we screened 50,240 structurally diverse small molecules from which we identified 104 compounds with anti-SARS-CoV activity. Of these 104 compounds, 2 target the SARS-CoV main protease (M(pro)), 7 target helicase (Hel), and 18 target spike (S) protein-angiotensin-converting enzyme 2 (ACE2)-mediated viral entry. The EC(50) of the majority of the 104 compounds determined by SARS-CoV plaque reduction assay were found to be at low micromolar range. Three selected compounds, MP576, HE602, and VE607, validated to be inhibitors of SARS-CoV M(pro), Hel, and viral entry, respectively, exhibited potent antiviral activity (EC(50) < 10 microM) and comparable inhibitory activities in target-specific in vitro assays.
Kao
Richard Y
RY
Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. ryykao@hkucc.hku.hk
Tsui
Wayne H W
WH
Lee
Terri S W
TS
Tanner
Julian A
JA
Watt
Rory M
RM
Huang
Jian-Dong
JD
Hu
Lihong
L
Chen
Guanhua
G
Chen
Zhiwei
Z
Zhang
Linqi
L
He
Tian
T
Chan
Kwok-Hung
KH
Tse
Herman
H
To
Amanda P C
AP
Ng
Louisa W Y
LW
Wong
Bonnie C W
BC
Tsoi
Hoi-Wah
HW
Yang
Dan
D
Ho
David D
DD
Yuen
Kwok-Yung
KY
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002522:Chlorocebus aethiops; D020650:Combinatorial Chemistry Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D007703:Peptidyl-Dipeptidase A; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy; D014709:Vero Cells; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D014763:Viral Matrix Proteins; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; D000085962:Angiotensin-Converting Enzyme 2