期刊
SLAS DISCOVERY
卷 26, 期 9, 页码 1200-1211出版社
ELSEVIER SCIENCE INC
DOI: 10.1177/24725552211026261
关键词
nsp14; SARS-CoV-2; COVID-19; coronavirus
资金
- University of Toronto COVID-19 Action Initiative-2020
- COVID-19 Mitacs Accelerate postdoctoral awards
- U.S. National Institutes of Health [R35GM131858]
- NIH/NIAID [HHSN2 72201700060C]
- AbbVie [1097737]
- Bayer AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Genentech [1097737]
- Genome Canada through Ontario Genomics Institute [1097737, OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant) [1097737, 875510]
- Janssen [1097737]
- Merck KGaA (aka EMD in Canada and the United States) [1097737]
- Pfizer [1097737]
- Takeda [1097737]
- Wellcome [1097737, 106169/ZZ14/Z]
The COVID-19 pandemic has severely affected global healthcare systems and led to devastating economic consequences. Research on small-molecule inhibitors targeting the nsp14 protein of SARS-CoV-2 virus may offer a path towards developing novel antivirals against COVID-19.
The COVID-19 pandemic has clearly brought the healthcare systems worldwide to a breaking point, along with devastating socioeconomic consequences. The SARS-CoV-2 virus, which causes the disease, uses RNA capping to evade the human immune system. Nonstructural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small-molecule inhibitors of nsp14 methyltransferase (MTase) activity, we developed and employed a radiometric MTase assay to screen a library of 161 in-house synthesized S-adenosylmethionine (SAM) competitive MTase inhibitors and SAM analogs. Among six identified screening hits, SS148 inhibited nsp14 MTase activity with an IC50 value of 70 +/- 6 nM and was selective against 20 human protein lysine MTases, indicating significant differences in SAM binding sites. Interestingly, DS0464 with an IC50 value of 1.1 +/- 0.2 mu M showed a bisubstrate competitive inhibitor mechanism of action. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein MTases. The structure-activity relationship provided by these compounds should guide the optimization of selective bisubstrate nsp14 inhibitors and may provide a path toward a novel class of antivirals against COVID-19, and possibly other coronaviruses.
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