Journal
ACS CHEMICAL BIOLOGY
Volume 17, Issue 1, Pages 17-23Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.1c00721
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- Johns Hopkins University
- Johns Hopkins Bloomberg School of Public Health Development Fund
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Viral macrodomains are crucial for virus replication and pathogenesis, making them a promising target for antiviral therapy. Dasatinib has been identified as a potential ADP-ribosylhydrolase inhibitor, showing effectiveness against SARS-CoV-2 and MERS-CoV, but not affecting the closest human homologue MacroD2. This study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity and provides a potential avenue for developing better macrodomain inhibitors as antiviral therapies for SARS-CoV-2 and other viral threats.
Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodomain inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen that identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib inhibits SARS-CoV-2 and MERS-CoV Mac1 but not the closest human homologue, MacroD2. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for the screening of large compound libraries to identify improved macrodomain inhibitors and to explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.
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