tetano
Editor, Senior Moderator
Antiviral Res
. 2022 May 19;105344.
doi: 10.1016/j.antiviral.2022.105344. Online ahead of print.
Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening
Anu Roy[SUP] 1 [/SUP], Yousef M Alhammad[SUP] 2 [/SUP], Peter McDonald[SUP] 1 [/SUP], David K Johnson[SUP] 3 [/SUP], Junlin Zhuo[SUP] 4 [/SUP], Sarah Wazir[SUP] 5 [/SUP], Dana Ferraris[SUP] 6 [/SUP], Lari Lehtiö[SUP] 5 [/SUP], Anthony K L Leung[SUP] 7 [/SUP], Anthony R Fehr[SUP] 8 [/SUP]
Affiliations
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 IC[SUB]50[/SUB] 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.
Keywords: ADP-Ribose; ADP-Ribosylation; Coronavirus; High-throughput screening; Macrodomain; SARS-CoV-2.
. 2022 May 19;105344.
doi: 10.1016/j.antiviral.2022.105344. Online ahead of print.
Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening
Anu Roy[SUP] 1 [/SUP], Yousef M Alhammad[SUP] 2 [/SUP], Peter McDonald[SUP] 1 [/SUP], David K Johnson[SUP] 3 [/SUP], Junlin Zhuo[SUP] 4 [/SUP], Sarah Wazir[SUP] 5 [/SUP], Dana Ferraris[SUP] 6 [/SUP], Lari Lehtiö[SUP] 5 [/SUP], Anthony K L Leung[SUP] 7 [/SUP], Anthony R Fehr[SUP] 8 [/SUP]
Affiliations
- PMID: 35598780
- DOI: 10.1016/j.antiviral.2022.105344
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 IC[SUB]50[/SUB] 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.
Keywords: ADP-Ribose; ADP-Ribosylation; Coronavirus; High-throughput screening; Macrodomain; SARS-CoV-2.