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Allosteric Inhibition of the SARS‐CoV‐2 Main Protease: Insights from Mass Spectrometry Based Assays
The SARS‐CoV‐2 main protease (Mpro) cleaves along the two viral polypeptides to release non‐structural proteins required for viral replication. MPro is an attractive target for antiviral therapies to combat the coronavirus‐2019 disease. Here, we used native mass spectrometry to characterize the func...
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| Published in: | Angewandte Chemie International Edition 2020-12, Vol.59 (52), p.23544-23548 |
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| creator | El‐Baba, Tarick J. Lutomski, Corinne A. Kantsadi, Anastassia L. Malla, Tika R. John, Tobias Mikhailov, Victor Bolla, Jani R. Schofield, Christopher J. Zitzmann, Nicole Vakonakis, Ioannis Robinson, Carol V. |
| description | The SARS‐CoV‐2 main protease (Mpro) cleaves along the two viral polypeptides to release non‐structural proteins required for viral replication. MPro is an attractive target for antiviral therapies to combat the coronavirus‐2019 disease. Here, we used native mass spectrometry to characterize the functional unit of Mpro. Analysis of the monomer/dimer equilibria reveals a dissociation constant of Kd=0.14±0.03 μM, indicating MPro has a strong preference to dimerize in solution. We characterized substrate turnover rates by following temporal changes in the enzyme‐substrate complexes, and screened small molecules, that bind distant from the active site, for their ability to modulate activity. These compounds, including one proposed to disrupt the dimer, slow the rate of substrate processing by ≈35 %. This information, together with analysis of the x‐ray crystal structures, provides a starting point for the development of more potent molecules that allosterically regulate MPro activity.
The SARS‐CoV‐2 main protease monomer/dimer equilibrium was characterized using native mass spectrometry. An MS‐based kinetic assay that quantifies the changes in the amounts of enzyme–substrate complex with time was used to capture MPro protease activity. Several small molecules bind non‐covalently to MPro, do not compete for the active site, and slow the processing of the substrate, providing a means for optimizing potential antiviral compounds. |
| doi_str_mv | 10.1002/anie.202010316 |
| format | article |
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The SARS‐CoV‐2 main protease monomer/dimer equilibrium was characterized using native mass spectrometry. An MS‐based kinetic assay that quantifies the changes in the amounts of enzyme–substrate complex with time was used to capture MPro protease activity. Several small molecules bind non‐covalently to MPro, do not compete for the active site, and slow the processing of the substrate, providing a means for optimizing potential antiviral compounds.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.202010316</identifier><identifier>PMID: 32841477</identifier><language>eng</language><publisher>Germany: John Wiley & Sons, Inc</publisher><subject>allosteric inhibitors ; Allosteric properties ; Allosteric Regulation ; Antiviral agents ; Binding Sites ; Biological Assay ; Communication ; Communications ; Coronavirus 3C Proteases - antagonists & inhibitors ; Coronavirus 3C Proteases - chemistry ; Coronavirus Protease Inhibitors - chemistry ; Coronavirus Protease Inhibitors - pharmacology ; Coronaviruses ; Crystal structure ; Crystallography, X-Ray ; Dimers ; drug development ; Information processing ; Mass Spectrometry ; Mass spectroscopy ; Models, Molecular ; native mass spectrometry ; Polypeptides ; Protease ; proteases ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Proteinase ; SARS-CoV-2 ; SARS-CoV-2 - enzymology ; SARS-CoV-2 - physiology ; Scientific imaging ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Spectroscopy ; Structural proteins ; Substrate Specificity ; Substrates ; Viral diseases ; Virus Replication</subject><ispartof>Angewandte Chemie International Edition, 2020-12, Vol.59 (52), p.23544-23548</ispartof><rights>2020 The Authors. Published by Wiley-VCH GmbH</rights><rights>2020 The Authors. Published by Wiley-VCH GmbH.</rights><rights>2020. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at https://novel-coronavirus.onlinelibrary.wiley.com</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5336-4f32ea96c138d339aa155f44499c3eb2b345bfdfc434cb43b42420f74f4df3633</citedby><cites>FETCH-LOGICAL-c5336-4f32ea96c138d339aa155f44499c3eb2b345bfdfc434cb43b42420f74f4df3633</cites><orcidid>0000-0001-7509-103X ; 0000-0002-4726-0446 ; 0000-0003-4497-9938 ; 0000-0001-7829-5505</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fanie.202010316$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2437039676?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,315,786,790,891,27957,27958,38551,43930,50923,51032</link.rule.ids><linktorsrc>$$Uhttps://www.proquest.com/docview/2437039676/abstract/?pq-origsite=primo$$EView_record_in_ProQuest$$FView_record_in_$$GProQuest</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32841477$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>El‐Baba, Tarick J.</creatorcontrib><creatorcontrib>Lutomski, Corinne A.</creatorcontrib><creatorcontrib>Kantsadi, Anastassia L.</creatorcontrib><creatorcontrib>Malla, Tika R.</creatorcontrib><creatorcontrib>John, Tobias</creatorcontrib><creatorcontrib>Mikhailov, Victor</creatorcontrib><creatorcontrib>Bolla, Jani R.</creatorcontrib><creatorcontrib>Schofield, Christopher J.</creatorcontrib><creatorcontrib>Zitzmann, Nicole</creatorcontrib><creatorcontrib>Vakonakis, Ioannis</creatorcontrib><creatorcontrib>Robinson, Carol V.</creatorcontrib><title>Allosteric Inhibition of the SARS‐CoV‐2 Main Protease: Insights from Mass Spectrometry Based Assays</title><title>Angewandte Chemie International Edition</title><addtitle>Angew Chem Int Ed Engl</addtitle><description>The SARS‐CoV‐2 main protease (Mpro) cleaves along the two viral polypeptides to release non‐structural proteins required for viral replication. MPro is an attractive target for antiviral therapies to combat the coronavirus‐2019 disease. Here, we used native mass spectrometry to characterize the functional unit of Mpro. Analysis of the monomer/dimer equilibria reveals a dissociation constant of Kd=0.14±0.03 μM, indicating MPro has a strong preference to dimerize in solution. We characterized substrate turnover rates by following temporal changes in the enzyme‐substrate complexes, and screened small molecules, that bind distant from the active site, for their ability to modulate activity. These compounds, including one proposed to disrupt the dimer, slow the rate of substrate processing by ≈35 %. This information, together with analysis of the x‐ray crystal structures, provides a starting point for the development of more potent molecules that allosterically regulate MPro activity.
The SARS‐CoV‐2 main protease monomer/dimer equilibrium was characterized using native mass spectrometry. An MS‐based kinetic assay that quantifies the changes in the amounts of enzyme–substrate complex with time was used to capture MPro protease activity. Several small molecules bind non‐covalently to MPro, do not compete for the active site, and slow the processing of the substrate, providing a means for optimizing potential antiviral compounds.</description><subject>allosteric inhibitors</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation</subject><subject>Antiviral agents</subject><subject>Binding Sites</subject><subject>Biological Assay</subject><subject>Communication</subject><subject>Communications</subject><subject>Coronavirus 3C Proteases - antagonists & inhibitors</subject><subject>Coronavirus 3C Proteases - chemistry</subject><subject>Coronavirus Protease Inhibitors - chemistry</subject><subject>Coronavirus Protease Inhibitors - pharmacology</subject><subject>Coronaviruses</subject><subject>Crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Dimers</subject><subject>drug development</subject><subject>Information processing</subject><subject>Mass Spectrometry</subject><subject>Mass spectroscopy</subject><subject>Models, Molecular</subject><subject>native mass spectrometry</subject><subject>Polypeptides</subject><subject>Protease</subject><subject>proteases</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Multimerization</subject><subject>Proteinase</subject><subject>SARS-CoV-2</subject><subject>SARS-CoV-2 - enzymology</subject><subject>SARS-CoV-2 - physiology</subject><subject>Scientific imaging</subject><subject>Severe acute respiratory syndrome</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Spectroscopy</subject><subject>Structural proteins</subject><subject>Substrate Specificity</subject><subject>Substrates</subject><subject>Viral diseases</subject><subject>Virus Replication</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>COVID</sourceid><recordid>eNqFkcuO0zAUhi0EYoaBLUtkiQ2bFNvnJE5YIIVqgErDRRTYWo5jtx6lcbFTUHc8As_Ik-BRh3JZwMYXnc-fzvFPyH3OZpwx8ViP3s4EE4wz4NUNcspLwQuQEm7mMwIUsi75CbmT0mXm65pVt8kJiBo5SnlKVu0whDTZ6A1djGvf-cmHkQZHp7Wly_bd8vvXb_PwMa-CvtJ-pG9jmKxO9knmk1-tp0RdDJtcTIkut9ZM-WanuKfPMtXTNiW9T3fJLaeHZO9d72fkw_Pz9_OXxcWbF4t5e1GYEqAq0IGwuqkMh7oHaLTmZekQsWkM2E50gGXnemcQ0HQIHQoUzEl02DuoAM7I04N3u-s2tjd2nKIe1Db6jY57FbRXf1ZGv1ar8FlJrHj-lSx4dC2I4dPOpkltfDJ2GPRowy4pgSCRYV03GX34F3oZdnHM42WqampEVuK_KZAMmkpWmZodKBNDStG6Y8ucqauk1VXS6ph0fvDg90GP-M9oM9AcgC9-sPv_6FT7enH-S_4D0F22HA</recordid><startdate>20201221</startdate><enddate>20201221</enddate><creator>El‐Baba, Tarick J.</creator><creator>Lutomski, Corinne A.</creator><creator>Kantsadi, Anastassia L.</creator><creator>Malla, Tika R.</creator><creator>John, Tobias</creator><creator>Mikhailov, Victor</creator><creator>Bolla, Jani R.</creator><creator>Schofield, Christopher J.</creator><creator>Zitzmann, Nicole</creator><creator>Vakonakis, Ioannis</creator><creator>Robinson, Carol V.</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>COVID</scope><scope>7TM</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7509-103X</orcidid><orcidid>https://orcid.org/0000-0002-4726-0446</orcidid><orcidid>https://orcid.org/0000-0003-4497-9938</orcidid><orcidid>https://orcid.org/0000-0001-7829-5505</orcidid></search><sort><creationdate>20201221</creationdate><title>Allosteric Inhibition of the SARS‐CoV‐2 Main Protease: Insights from Mass Spectrometry Based Assays</title><author>El‐Baba, Tarick J. ; Lutomski, Corinne A. ; Kantsadi, Anastassia L. ; Malla, Tika R. ; John, Tobias ; Mikhailov, Victor ; Bolla, Jani R. ; Schofield, Christopher J. ; Zitzmann, Nicole ; Vakonakis, Ioannis ; Robinson, Carol V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5336-4f32ea96c138d339aa155f44499c3eb2b345bfdfc434cb43b42420f74f4df3633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>allosteric inhibitors</topic><topic>Allosteric properties</topic><topic>Allosteric Regulation</topic><topic>Antiviral agents</topic><topic>Binding Sites</topic><topic>Biological Assay</topic><topic>Communication</topic><topic>Communications</topic><topic>Coronavirus 3C Proteases - antagonists & inhibitors</topic><topic>Coronavirus 3C Proteases - chemistry</topic><topic>Coronavirus Protease Inhibitors - chemistry</topic><topic>Coronavirus Protease Inhibitors - pharmacology</topic><topic>Coronaviruses</topic><topic>Crystal structure</topic><topic>Crystallography, X-Ray</topic><topic>Dimers</topic><topic>drug development</topic><topic>Information processing</topic><topic>Mass Spectrometry</topic><topic>Mass spectroscopy</topic><topic>Models, Molecular</topic><topic>native mass spectrometry</topic><topic>Polypeptides</topic><topic>Protease</topic><topic>proteases</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protein Multimerization</topic><topic>Proteinase</topic><topic>SARS-CoV-2</topic><topic>SARS-CoV-2 - enzymology</topic><topic>SARS-CoV-2 - physiology</topic><topic>Scientific imaging</topic><topic>Severe acute respiratory syndrome</topic><topic>Severe acute respiratory syndrome coronavirus 2</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Spectroscopy</topic><topic>Structural proteins</topic><topic>Substrate Specificity</topic><topic>Substrates</topic><topic>Viral diseases</topic><topic>Virus Replication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>El‐Baba, Tarick J.</creatorcontrib><creatorcontrib>Lutomski, Corinne A.</creatorcontrib><creatorcontrib>Kantsadi, Anastassia L.</creatorcontrib><creatorcontrib>Malla, Tika R.</creatorcontrib><creatorcontrib>John, Tobias</creatorcontrib><creatorcontrib>Mikhailov, Victor</creatorcontrib><creatorcontrib>Bolla, Jani R.</creatorcontrib><creatorcontrib>Schofield, Christopher J.</creatorcontrib><creatorcontrib>Zitzmann, Nicole</creatorcontrib><creatorcontrib>Vakonakis, Ioannis</creatorcontrib><creatorcontrib>Robinson, Carol V.</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Coronavirus Research Database</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>El‐Baba, Tarick J.</au><au>Lutomski, Corinne A.</au><au>Kantsadi, Anastassia L.</au><au>Malla, Tika R.</au><au>John, Tobias</au><au>Mikhailov, Victor</au><au>Bolla, Jani R.</au><au>Schofield, Christopher J.</au><au>Zitzmann, Nicole</au><au>Vakonakis, Ioannis</au><au>Robinson, Carol V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Allosteric Inhibition of the SARS‐CoV‐2 Main Protease: Insights from Mass Spectrometry Based Assays</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew Chem Int Ed Engl</addtitle><date>2020-12-21</date><risdate>2020</risdate><volume>59</volume><issue>52</issue><spage>23544</spage><epage>23548</epage><pages>23544-23548</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><notes>https://doi.org/10.1101/2020.07.29.226761</notes><notes>.</notes><notes>A previous version of this manuscript has been deposited on a preprint server</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>A previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.1101/2020.07.29.226761).</notes><abstract>The SARS‐CoV‐2 main protease (Mpro) cleaves along the two viral polypeptides to release non‐structural proteins required for viral replication. MPro is an attractive target for antiviral therapies to combat the coronavirus‐2019 disease. Here, we used native mass spectrometry to characterize the functional unit of Mpro. Analysis of the monomer/dimer equilibria reveals a dissociation constant of Kd=0.14±0.03 μM, indicating MPro has a strong preference to dimerize in solution. We characterized substrate turnover rates by following temporal changes in the enzyme‐substrate complexes, and screened small molecules, that bind distant from the active site, for their ability to modulate activity. These compounds, including one proposed to disrupt the dimer, slow the rate of substrate processing by ≈35 %. This information, together with analysis of the x‐ray crystal structures, provides a starting point for the development of more potent molecules that allosterically regulate MPro activity.
The SARS‐CoV‐2 main protease monomer/dimer equilibrium was characterized using native mass spectrometry. An MS‐based kinetic assay that quantifies the changes in the amounts of enzyme–substrate complex with time was used to capture MPro protease activity. Several small molecules bind non‐covalently to MPro, do not compete for the active site, and slow the processing of the substrate, providing a means for optimizing potential antiviral compounds.</abstract><cop>Germany</cop><pub>John Wiley & Sons, Inc</pub><pmid>32841477</pmid><doi>10.1002/anie.202010316</doi><tpages>5</tpages><edition>International ed. in English</edition><orcidid>https://orcid.org/0000-0001-7509-103X</orcidid><orcidid>https://orcid.org/0000-0002-4726-0446</orcidid><orcidid>https://orcid.org/0000-0003-4497-9938</orcidid><orcidid>https://orcid.org/0000-0001-7829-5505</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | allosteric inhibitors Allosteric properties Allosteric Regulation Antiviral agents Binding Sites Biological Assay Communication Communications Coronavirus 3C Proteases - antagonists & inhibitors Coronavirus 3C Proteases - chemistry Coronavirus Protease Inhibitors - chemistry Coronavirus Protease Inhibitors - pharmacology Coronaviruses Crystal structure Crystallography, X-Ray Dimers drug development Information processing Mass Spectrometry Mass spectroscopy Models, Molecular native mass spectrometry Polypeptides Protease proteases Protein Binding Protein Conformation Protein Multimerization Proteinase SARS-CoV-2 SARS-CoV-2 - enzymology SARS-CoV-2 - physiology Scientific imaging Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Spectroscopy Structural proteins Substrate Specificity Substrates Viral diseases Virus Replication |
| title | Allosteric Inhibition of the SARS‐CoV‐2 Main Protease: Insights from Mass Spectrometry Based Assays |
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