Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening
Roy, Anu; Alhammad, Yousef M.; McDonald, Peter; Johnson, David K.; Zhuo, Junlin; Wazir, Sarah; Ferraris, Dana; Lehtiö, Lari; Leung, Anthony K. L.; Fehr, Anthony R. (2022-05-19)
Anu Roy, Yousef M. Alhammad, Peter McDonald, David K. Johnson, Junlin Zhuo, Sarah Wazir, Dana Ferraris, Lari Lehtiö, Anthony K.L. Leung, Anthony R. Fehr, Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening, Antiviral Research, Volume 203, 2022, 105344, ISSN 0166-3542, https://doi.org/10.1016/j.antiviral.2022.105344
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https://urn.fi/URN:NBN:fi-fe2023020225594
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Abstract
The emergence of several zoonotic viruses in the last twenty years, especially the pandemic outbreak of SARS-CoV-2, has exposed a dearth of antiviral drug therapies for viruses with pandemic potential. Developing a diverse drug portfolio will be critical to rapidly respond to novel coronaviruses (CoVs) and other viruses with pandemic potential. Here we focus on the SARS-CoV-2 conserved macrodomain (Mac1), a small domain of non-structural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that cleaves mono-ADP-ribose (MAR) from target proteins, protects the virus from the anti-viral effects of host ADP-ribosyltransferases, and is critical for the replication and pathogenesis of CoVs. In this study, a luminescent-based high-throughput assay was used to screen ∼38,000 small molecules for those that could inhibit Mac1-ADP-ribose binding. We identified 5 compounds amongst 3 chemotypes that inhibit SARS-CoV-2 Mac1-ADP-ribose binding in multiple assays with IC₅₀ values less than 100 μM, inhibit ADP-ribosylhydrolase activity, and have evidence of direct Mac1 binding. These chemotypes are strong candidates for further derivatization into highly effective Mac1 inhibitors.
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