title: Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics.
abstract: 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.
authors.affiliation: Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. ryykao@hkucc.hku.hk
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Kao
authors.forename: Wayne H W
authors.initials: WH
authors.lastname: Tsui
authors.forename: Terri S W
authors.initials: TS
authors.lastname: Lee
authors.forename: Julian A
authors.initials: JA
authors.lastname: Tanner
authors.forename: Rory M
authors.initials: RM
authors.lastname: Watt
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Huang
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
authors.forename: Guanhua
authors.initials: G
authors.lastname: Chen
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
authors.forename: Tian
authors.initials: T
authors.lastname: He
authors.forename: Kwok-Hung
authors.initials: KH
authors.lastname: Chan
authors.forename: Herman
authors.initials: H
authors.lastname: Tse
authors.forename: Amanda P C
authors.initials: AP
authors.lastname: To
authors.forename: Louisa W Y
authors.initials: LW
authors.lastname: Ng
authors.forename: Bonnie C W
authors.initials: BC
authors.lastname: Wong
authors.forename: Hoi-Wah
authors.initials: HW
authors.lastname: Tsoi
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: 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
chemical_list: D000998:Antiviral Agents; D014763:Viral Matrix Proteins; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; D000085962:Angiotensin-Converting Enzyme 2