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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin-Converting Enzyme 2
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Animals
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacology*
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Carboxypeptidases / antagonists & inhibitors
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Carboxypeptidases / metabolism
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Chlorocebus aethiops
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Combinatorial Chemistry Techniques
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Models, Molecular
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Molecular Structure
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Peptidyl-Dipeptidase A
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Severe Acute Respiratory Syndrome / drug therapy
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Severe acute respiratory syndrome-related coronavirus / drug effects*
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Severe acute respiratory syndrome-related coronavirus / growth & development
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Severe acute respiratory syndrome-related coronavirus / metabolism
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Severe acute respiratory syndrome-related coronavirus / physiology
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Vero Cells
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Viral Matrix Proteins / antagonists & inhibitors
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Viral Matrix Proteins / metabolism
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Viral Matrix Proteins
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Carboxypeptidases
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Peptidyl-Dipeptidase A
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Angiotensin-Converting Enzyme 2