tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Junlin Zhuo[SUP] 1 [/SUP], Jack A Goodman[SUP] 1 [/SUP], Ajit Thomas[SUP] 3 4 [/SUP], Robert Lyle McPherson[SUP] 1 [/SUP], Aravinth Kumar Jayabalan[SUP] 1 [/SUP], Veronica F Busa[SUP] 1 [/SUP], Shang-Jung Cheng[SUP] 1 [/SUP], Brennan A Murphy[SUP] 3 [/SUP], Karli R Redinger[SUP] 5 [/SUP], Yousef M O Alhammad[SUP] 6 [/SUP], Anthony R Fehr[SUP] 6 [/SUP], Takashi Tsukamoto[SUP] 3 4 [/SUP], Barbara S Slusher[SUP] 3 4 [/SUP], Jürgen Bosch[SUP] 5 7 [/SUP], Huijun Wei[SUP] 3 4 [/SUP], Anthony K L Leung[SUP] 1 [/SUP]
Affiliations
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.
. 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[SUP] 1 2 [/SUP], Junlin Zhuo[SUP] 1 [/SUP], Jack A Goodman[SUP] 1 [/SUP], Ajit Thomas[SUP] 3 4 [/SUP], Robert Lyle McPherson[SUP] 1 [/SUP], Aravinth Kumar Jayabalan[SUP] 1 [/SUP], Veronica F Busa[SUP] 1 [/SUP], Shang-Jung Cheng[SUP] 1 [/SUP], Brennan A Murphy[SUP] 3 [/SUP], Karli R Redinger[SUP] 5 [/SUP], Yousef M O Alhammad[SUP] 6 [/SUP], Anthony R Fehr[SUP] 6 [/SUP], Takashi Tsukamoto[SUP] 3 4 [/SUP], Barbara S Slusher[SUP] 3 4 [/SUP], Jürgen Bosch[SUP] 5 7 [/SUP], Huijun Wei[SUP] 3 4 [/SUP], Anthony K L Leung[SUP] 1 [/SUP]
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.