Probing the SAM Binding Site of SARS-CoV-2 Nsp14 In Vitro Using SAM Competitive Inhibitors Guides Developing Selective Bisubstrate Inhibitors Open Access (recommended)
Descriptions
- Resource type(s)
- Article
- Keyword
- COVID-19
nsp14
SARS-CoV-2
coronavirus
- Rights
- Attribution-NonCommercial 3.0 United States
- Creator
-
Devkota, Kanchan
Schapira, Matthieu
Perveen, Sumera
Yazdi, Aliakbar Khalili
Li, Fengling
Chau, Irene
Ghiabi, Pegah
Hajian, Taraneh
Loppnau, Peter
Bolotokova, Albina
Satchell, Karla J. F.
Wang, Ke
Li, Deyao
Liu, Jing
Smil, David
Luo, Minkui
Jin, Jian
Fish, Paul, V.
Brown, Peter J.
Vedadi, Masoud
- Abstract
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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.
- Original Bibliographic Citation
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Devkota K, Schapira M, Perveen S, Yazdi AK, Li FL, Chau I, Ghiabi P, Hajian T, Loppnau P, Bolotokova A, Satchell KJF, Wang K, Li DY, Liu J, Smil D, Luo MK, Jin J, Fish PV, Brown PJ, Vedadi M. Probing the SAM Binding Site of SARS-CoV-2 Nsp14 In Vitro Using SAM Competitive Inhibitors Guides Developing Selective Bisubstrate Inhibitors. Slas Discovery. 2021;26(9):1200-1211.
- Related URL
- Publisher
-
SAGE PUBLICATIONS INC
- Date Created
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2021-10
- Original Identifier
- (PMID) 34192965
- Language
- English
- Subject: MESH
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SARS-CoV-2
COVID-19
S-Adenosylmethionine
Binding Sites
- Grants and funding
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University of Toronto COVID-19 Action Initiative-2020; COVID-19 Mitacs Accelerate postdoctoral awards; U.S. National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R35GM131858]; NIH/NIAIDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [HHSN2 72201700060C]; AbbVieAbbVie [1097737]; Bayer AGBayer AG [1097737]; Boehringer IngelheimBoehringer Ingelheim [1097737]; Canada Foundation for InnovationCanada Foundation for InnovationCGIAR [1097737]; GenentechRoche HoldingGenentech [1097737]; Genome Canada through Ontario Genomics InstituteGenome Canada [1097737, OGI-196]; EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant) [1097737, 875510]; JanssenJohnson & JohnsonJohnson & Johnson USAJanssen Biotech Inc [1097737]; Merck KGaA (aka EMD in Canada and the United States) [1097737]; PfizerPfizer [1097737]; TakedaTakeda Pharmaceutical Company Ltd [1097737]; Wellcome [1097737, 106169/ZZ14/Z]
- DOI
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10.1177/24725552211026261
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