High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain

Dasovich, M.; Zhuo, J.; Goodman, J.A.; Thomas, A.; McPherson, R.L.; Jayabalan, A.K.; Busa, V.F.; Cheng, S.-J.; Murphy, B.A.; Redinger, K.R.; Alhammad, Y.M.O.; Fehr, A.R.; Tsukamoto, T.; Slusher, B.S.; Bosch, J. ✉; Wei, H. ✉; Leung, A.K.L. ✉

Angol nyelvű Szakcikk (Folyóiratcikk) Tudományos
  • SJR Scopus - Medicine (miscellaneous): D1
Azonosítók
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. © XXXX American Chemical Society.
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2024-02-28 06:41