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ACS Chem Biol
. 2021 Dec 14.
doi: 10.1021/acschembio.1c00721. Online ahead of print.
High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain
Morgan Dasovich 1 2 , Junlin Zhuo 1 , Jack A Goodman 1 , Ajit Thomas 3 4 , Robert Lyle McPherson 1 , Aravinth Kumar Jayabalan 1 , Veronica F Busa 1 , Shang-Jung Cheng 1 , Brennan A Murphy 3 , Karli R Redinger 5 , Yousef M O Alhammad 6 , Anthony R Fehr 6 , Takashi Tsukamoto 3 4 , Barbara S Slusher 3 4 , Jürgen Bosch 5 7 , Huijun Wei 3 4 , Anthony K L Leung 1
Affiliations
- PMID: 34904435
- DOI: 10.1021/acschembio.1c00721
Abstract
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.