Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors by High-Throughput Virtual Screening

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agent...

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Published in:	Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 12; p. 1243
Main Authors:	Bobrovs, Raitis, Kanepe, Iveta, Narvaiss, Nauris, Patetko, Liene, Kalnins, Gints, Sisovs, Mihails, Bula, Anna L., Grinberga, Solveiga, Boroduskis, Martins, Ramata-Stunda, Anna, Rostoks, Nils, Jirgensons, Aigars, Tars, Kaspars, Jaudzems, Kristaps
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 30.11.2021 MDPI
Subjects:	Amino acids antiviral drugs Binding sites Coronaviruses COVID-19 Enzymes Epidemics high-throughput virtual screening Hydrogen bonds Immune system Ligands Middle East respiratory syndrome MTase inhibitors nsp14 nsp16 Respiratory diseases SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 antiviral drugs SARS-CoV-2 nsp14 high-throughput virtual screening MTase inhibitors nsp16
ISSN:	1424-8247, 1424-8247
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Abstract	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC50 < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors.
AbstractList	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC50 < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC50 < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC50 < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors.
Author	Ramata-Stunda, Anna Tars, Kaspars Jaudzems, Kristaps Patetko, Liene Kalnins, Gints Kanepe, Iveta Boroduskis, Martins Bula, Anna L. Narvaiss, Nauris Bobrovs, Raitis Grinberga, Solveiga Jirgensons, Aigars Rostoks, Nils Sisovs, Mihails
AuthorAffiliation	2 Faculty of Biology, University of Latvia, Jelgavas 1, LV-1004 Riga, Latvia; liene.patetko@gmail.com (L.P.); martins.boroduskis@lu.lv (M.B.); anna.ramata-stunda@lu.lv (A.R.-S.); nils.rostoks@lu.lv (N.R.) 1 Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia; iveta@farm.osi.lv (I.K.); nauris.narvaiss@osi.lv (N.N.); anna.lina.bula@osi.lv (A.L.B.); solveiga@osi.lv (S.G.); aigars@osi.lv (A.J.); kristaps.jaudzems@osi.lv (K.J.) 3 Latvian Biomedical Research and Study Centre, Ratsupites 1 k1, LV-1067 Riga, Latvia; gints.kalnins@biomed.lu.lv (G.K.); mihails.shishovs@gmail.com (M.S.); kaspars@biomed.lu.lv (K.T.)
AuthorAffiliation_xml	– name: 2 Faculty of Biology, University of Latvia, Jelgavas 1, LV-1004 Riga, Latvia; liene.patetko@gmail.com (L.P.); martins.boroduskis@lu.lv (M.B.); anna.ramata-stunda@lu.lv (A.R.-S.); nils.rostoks@lu.lv (N.R.) – name: 1 Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia; iveta@farm.osi.lv (I.K.); nauris.narvaiss@osi.lv (N.N.); anna.lina.bula@osi.lv (A.L.B.); solveiga@osi.lv (S.G.); aigars@osi.lv (A.J.); kristaps.jaudzems@osi.lv (K.J.) – name: 3 Latvian Biomedical Research and Study Centre, Ratsupites 1 k1, LV-1067 Riga, Latvia; gints.kalnins@biomed.lu.lv (G.K.); mihails.shishovs@gmail.com (M.S.); kaspars@biomed.lu.lv (K.T.)
Author_xml	– sequence: 1 givenname: Raitis orcidid: 0000-0002-0221-8658 surname: Bobrovs fullname: Bobrovs, Raitis – sequence: 2 givenname: Iveta surname: Kanepe fullname: Kanepe, Iveta – sequence: 3 givenname: Nauris surname: Narvaiss fullname: Narvaiss, Nauris – sequence: 4 givenname: Liene surname: Patetko fullname: Patetko, Liene – sequence: 5 givenname: Gints surname: Kalnins fullname: Kalnins, Gints – sequence: 6 givenname: Mihails surname: Sisovs fullname: Sisovs, Mihails – sequence: 7 givenname: Anna L. surname: Bula fullname: Bula, Anna L. – sequence: 8 givenname: Solveiga surname: Grinberga fullname: Grinberga, Solveiga – sequence: 9 givenname: Martins surname: Boroduskis fullname: Boroduskis, Martins – sequence: 10 givenname: Anna orcidid: 0000-0003-0097-0931 surname: Ramata-Stunda fullname: Ramata-Stunda, Anna – sequence: 11 givenname: Nils orcidid: 0000-0002-4047-2438 surname: Rostoks fullname: Rostoks, Nils – sequence: 12 givenname: Aigars surname: Jirgensons fullname: Jirgensons, Aigars – sequence: 13 givenname: Kaspars surname: Tars fullname: Tars, Kaspars – sequence: 14 givenname: Kristaps orcidid: 0000-0003-3922-2447 surname: Jaudzems fullname: Jaudzems, Kristaps
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SubjectTerms	Amino acids antiviral drugs Binding sites Coronaviruses COVID-19 Enzymes Epidemics high-throughput virtual screening Hydrogen bonds Immune system Ligands Middle East respiratory syndrome MTase inhibitors nsp14 nsp16 Respiratory diseases SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
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Title	Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors by High-Throughput Virtual Screening
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