Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics

Chemistry & Biology
Richard Y KaoKwok-Yung Yuen

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.

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Methods Mentioned

BETA
electrophoresis
dissection
affinity purification
Assay

Software Mentioned

CHARMM
SigmaPlot
ImageQuaNT
Autodock
InsightII
Sybyl
Cerius2 LigandFit
Chem3D
SPSS
Autodock3

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