posted on 2021-12-14, 13:05authored byMorgan Dasovich, Junlin Zhuo, Jack A. Goodman, Ajit Thomas, Robert Lyle McPherson, Aravinth Kumar Jayabalan, Veronica F. Busa, Shang-Jung Cheng, Brennan A. Murphy, Karli R. Redinger, Yousef M. O. Alhammad, Anthony R. Fehr, Takashi Tsukamoto, Barbara S. Slusher, Jürgen Bosch, Huijun Wei, Anthony K. L. Leung
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.