Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1002/anie.202205858 http://hdl.handle.net/11449/246060 |
Resumo: | SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome. |
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Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug DevelopmentCOVID19-NMRDrug DiscoveryFragment ScreeningNMR SpectroscopyProteinSARS-CoV-2SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.Fondazione Cassa di Risparmio di FirenzeHessisches Ministerium für Wissenschaft und KunstH2020 Future and Emerging TechnologiesDeutsche ForschungsgemeinschaftH2020 Research InfrastructuresFP7 Research Potential of Convergence RegionsNational Science FoundationKey Laboratory of Dynamic Cognitive System of Electromagnetic Spectrum SpaceKrebsliga SchweizAgence Nationale de la RechercheNational Institutes of HealthSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungInstitute for Organic Chemistry and Chemical Biology Goethe University FrankfurtCenter of Biomolecular Magnetic Resonance (BMRZ) Goethe University Frankfurt Frankfurt am Main (Germany), Max-von-LaueStrasse 7+9Institute for Molecular Biosciences Goethe University Frankfurt, Max-von-Laue Strasse 7+9Saverna Therapeutics, Pumpmattenweg 3Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) Screening Port, Schnackenburgallee 114Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Theodor-Stern-Kai 7Institute of Medical Biochemistry Federal University of Rio de JaneiroNational Center of Nuclear Magnetic Resonance (CNRMN) CENABIO Federal University of Rio de JaneiroDepartment of Biochemistry Institute of Chemistry Federal University of Rio de JaneiroLatvian Institute of Organic Synthesis, Aizkraukles 21ETH Swiss Federal Institute of Technology Laboratory of Physical Chemistry HCI F217, Vladimir-Prelog-Weg 2Multiuser Center for Biomolecular Innovation (CMIB) Department of Physics São Paulo State University (UNESP)Magnetic Resonance Center (CERM) University of Florence, Via Luigi Sacconi 6, Sesto FiorentinoDepartment of Chemistry “Ugo Schiff” University of Florence, Via della Lastruccia 3-13, Sesto FiorentinoMultidisciplinary Center for Research in Biology (NUMPEX), Campus Duque de Caxias Federal University of Rio de JaneiroDepartment of Pharmacy University of PatrasDepartment of Chemistry University of TorinoLaboratory of Toxinology Oswaldo Cruz Foundation (FIOCRUZ)Department of Molecular Biology and Biophysics UConn Health, 263 Farmington Ave.Department of Biochemistry University of Wisconsin-MadisonMolecular Microbiology and Structural Biochemistry UMR5086 CNRS/Université Lyon 1, 7, passage du Vercors“Rocasolano” Institute for Physical Chemistry CSICLaboratory of Chemical Physics National Institute of Diabetes and Digestive and KidneyUniversity of Vienna Department of Pharmaceutical Sciences, Josef-Holaubek-Platz 2Department of Biology Technical University of DarmstadtMultiuser Center for Biomolecular Innovation (CMIB) Department of Physics São Paulo State University (UNESP)H2020 Future and Emerging Technologies: 101046203Deutsche Forschungsgemeinschaft: 277478796Deutsche Forschungsgemeinschaft: 277479031Deutsche Forschungsgemeinschaft: 392682309Deutsche Forschungsgemeinschaft: 452632086Deutsche Forschungsgemeinschaft: 70653611H2020 Research Infrastructures: 871037Deutsche Forschungsgemeinschaft: CRC 902Deutsche Forschungsgemeinschaft: CRC902FP7 Research Potential of Convergence Regions: CT-2011-285950National Science Foundation: DBI 2030601National Science Foundation: EAGER MCB-2031269Key Laboratory of Dynamic Cognitive System of Electromagnetic Spectrum Space: FISR2020IP_02112Hessisches Ministerium für Wissenschaft und Kunst: IWB-EFRE-program 20007375Krebsliga Schweiz: KFS-4903-08-2019Agence Nationale de la Recherche: NMR-SCoV2-ORF8National Institutes of Health: P41GM111135National Institutes of Health: R01GM123249National Institutes of Health: R01GM135592Deutsche Forschungsgemeinschaft: SCHL2062/2-1Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung: SNF-310030_192646Goethe University FrankfurtFrankfurt am Main (Germany)Saverna TherapeuticsScreening PortFraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD)Federal University of Rio de JaneiroLatvian Institute of Organic SynthesisHCI F217Universidade Estadual Paulista (UNESP)University of FlorenceMultidisciplinary Center for Research in Biology (NUMPEX)University of PatrasUniversity of TorinoOswaldo Cruz Foundation (FIOCRUZ)UConn HealthUniversity of Wisconsin-MadisonUMR5086 CNRS/Université Lyon 1CSICNational Institute of Diabetes and Digestive and KidneyUniversity of ViennaTechnical University of DarmstadtBerg, HannesWirtz Martin, Maria A.Altincekic, NadideAlshamleh, IslamKaur Bains, JasleenBlechar, JuliusCeylan, Betülde Jesus, VanessaDhamotharan, KarthikeyanFuks, ChristinGande, Santosh L.Hargittay, BrunoHohmann, Katharina F.Hutchison, Marie T.Marianne Korn, SophieKrishnathas, RobinKutz, FelicitasLinhard, VerenaMatzel, TobiasMeiser, NathalieNiesteruk, AnnaPyper, Dennis J.Schulte, LindaTrucks, SvenAzzaoui, KamalBlommers, Marcel J. J.Gadiya, YojanaKarki, ReagonZaliani, AndreaGribbon, Philipda Silva Almeida, MarciusDinis Anobom, CristianeBula, Anna L.Bütikofer, MatthiasPutinhon Caruso, Ícaro [UNESP]Caterina Felli, IsabellaDa Poian, Andrea T.Cardoso de Amorim, GiseleFourkiotis, Nikolaos K.Gallo, AngeloGhosh, DhimanGomes-Neto, FranciscoGorbatyuk, OksanaHao, BingKurauskas, ViliusLecoq, LaurianeLi, YunfengCunha Mebus-Antunes, NathaneMompeán, MiguelCristtina Neves-Martins, ThaisNinot-Pedrosa, MartíPinheiro, Anderson S.Pontoriero, LetiziaPustovalova, YuliaRiek, RolandRobertson, Angus J.Jose Abi Saad, MarieTreviño, Miguel Á.Tsika, Aikaterini C.Almeida, Fabio C. L.Bax, AdHenzler-Wildman, KatherineHoch, Jeffrey C.Jaudzems, KristapsLaurents, Douglas V.Orts, JulienPierattelli, RobertaSpyroulias, Georgios A.Duchardt-Ferner, ElkeFerner, JanFürtig, BorisHengesbach, MartinLöhr, FrankQureshi, NusratRichter, ChristianSaxena, KrishnaSchlundt, AndreasSreeramulu, SridharWacker, AnnaWeigand, Julia E.Wirmer-Bartoschek, JuliaWöhnert, JensSchwalbe, Harald2023-07-29T12:30:39Z2023-07-29T12:30:39Z2022-11-14info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1002/anie.202205858Angewandte Chemie - International Edition, v. 61, n. 46, 2022.1521-37731433-7851http://hdl.handle.net/11449/24606010.1002/anie.2022058582-s2.0-85139756352Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengAngewandte Chemie - International Editioninfo:eu-repo/semantics/openAccess2023-07-29T12:30:40Zoai:repositorio.unesp.br:11449/246060Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462023-07-29T12:30:40Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development |
title |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development |
spellingShingle |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development Berg, Hannes COVID19-NMR Drug Discovery Fragment Screening NMR Spectroscopy Protein SARS-CoV-2 |
title_short |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development |
title_full |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development |
title_fullStr |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development |
title_full_unstemmed |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development |
title_sort |
Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development |
author |
Berg, Hannes |
author_facet |
Berg, Hannes Wirtz Martin, Maria A. Altincekic, Nadide Alshamleh, Islam Kaur Bains, Jasleen Blechar, Julius Ceylan, Betül de Jesus, Vanessa Dhamotharan, Karthikeyan Fuks, Christin Gande, Santosh L. Hargittay, Bruno Hohmann, Katharina F. Hutchison, Marie T. Marianne Korn, Sophie Krishnathas, Robin Kutz, Felicitas Linhard, Verena Matzel, Tobias Meiser, Nathalie Niesteruk, Anna Pyper, Dennis J. Schulte, Linda Trucks, Sven Azzaoui, Kamal Blommers, Marcel J. J. Gadiya, Yojana Karki, Reagon Zaliani, Andrea Gribbon, Philip da Silva Almeida, Marcius Dinis Anobom, Cristiane Bula, Anna L. Bütikofer, Matthias Putinhon Caruso, Ícaro [UNESP] Caterina Felli, Isabella Da Poian, Andrea T. Cardoso de Amorim, Gisele Fourkiotis, Nikolaos K. Gallo, Angelo Ghosh, Dhiman Gomes-Neto, Francisco Gorbatyuk, Oksana Hao, Bing Kurauskas, Vilius Lecoq, Lauriane Li, Yunfeng Cunha Mebus-Antunes, Nathane Mompeán, Miguel Cristtina Neves-Martins, Thais Ninot-Pedrosa, Martí Pinheiro, Anderson S. Pontoriero, Letizia Pustovalova, Yulia Riek, Roland Robertson, Angus J. Jose Abi Saad, Marie Treviño, Miguel Á. Tsika, Aikaterini C. Almeida, Fabio C. L. Bax, Ad Henzler-Wildman, Katherine Hoch, Jeffrey C. Jaudzems, Kristaps Laurents, Douglas V. Orts, Julien Pierattelli, Roberta Spyroulias, Georgios A. Duchardt-Ferner, Elke Ferner, Jan Fürtig, Boris Hengesbach, Martin Löhr, Frank Qureshi, Nusrat Richter, Christian Saxena, Krishna Schlundt, Andreas Sreeramulu, Sridhar Wacker, Anna Weigand, Julia E. Wirmer-Bartoschek, Julia Wöhnert, Jens Schwalbe, Harald |
author_role |
author |
author2 |
Wirtz Martin, Maria A. Altincekic, Nadide Alshamleh, Islam Kaur Bains, Jasleen Blechar, Julius Ceylan, Betül de Jesus, Vanessa Dhamotharan, Karthikeyan Fuks, Christin Gande, Santosh L. Hargittay, Bruno Hohmann, Katharina F. Hutchison, Marie T. Marianne Korn, Sophie Krishnathas, Robin Kutz, Felicitas Linhard, Verena Matzel, Tobias Meiser, Nathalie Niesteruk, Anna Pyper, Dennis J. Schulte, Linda Trucks, Sven Azzaoui, Kamal Blommers, Marcel J. J. Gadiya, Yojana Karki, Reagon Zaliani, Andrea Gribbon, Philip da Silva Almeida, Marcius Dinis Anobom, Cristiane Bula, Anna L. Bütikofer, Matthias Putinhon Caruso, Ícaro [UNESP] Caterina Felli, Isabella Da Poian, Andrea T. Cardoso de Amorim, Gisele Fourkiotis, Nikolaos K. Gallo, Angelo Ghosh, Dhiman Gomes-Neto, Francisco Gorbatyuk, Oksana Hao, Bing Kurauskas, Vilius Lecoq, Lauriane Li, Yunfeng Cunha Mebus-Antunes, Nathane Mompeán, Miguel Cristtina Neves-Martins, Thais Ninot-Pedrosa, Martí Pinheiro, Anderson S. Pontoriero, Letizia Pustovalova, Yulia Riek, Roland Robertson, Angus J. Jose Abi Saad, Marie Treviño, Miguel Á. Tsika, Aikaterini C. Almeida, Fabio C. L. Bax, Ad Henzler-Wildman, Katherine Hoch, Jeffrey C. Jaudzems, Kristaps Laurents, Douglas V. Orts, Julien Pierattelli, Roberta Spyroulias, Georgios A. Duchardt-Ferner, Elke Ferner, Jan Fürtig, Boris Hengesbach, Martin Löhr, Frank Qureshi, Nusrat Richter, Christian Saxena, Krishna Schlundt, Andreas Sreeramulu, Sridhar Wacker, Anna Weigand, Julia E. Wirmer-Bartoschek, Julia Wöhnert, Jens Schwalbe, Harald |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Goethe University Frankfurt Frankfurt am Main (Germany) Saverna Therapeutics Screening Port Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD) Federal University of Rio de Janeiro Latvian Institute of Organic Synthesis HCI F217 Universidade Estadual Paulista (UNESP) University of Florence Multidisciplinary Center for Research in Biology (NUMPEX) University of Patras University of Torino Oswaldo Cruz Foundation (FIOCRUZ) UConn Health University of Wisconsin-Madison UMR5086 CNRS/Université Lyon 1 CSIC National Institute of Diabetes and Digestive and Kidney University of Vienna Technical University of Darmstadt |
dc.contributor.author.fl_str_mv |
Berg, Hannes Wirtz Martin, Maria A. Altincekic, Nadide Alshamleh, Islam Kaur Bains, Jasleen Blechar, Julius Ceylan, Betül de Jesus, Vanessa Dhamotharan, Karthikeyan Fuks, Christin Gande, Santosh L. Hargittay, Bruno Hohmann, Katharina F. Hutchison, Marie T. Marianne Korn, Sophie Krishnathas, Robin Kutz, Felicitas Linhard, Verena Matzel, Tobias Meiser, Nathalie Niesteruk, Anna Pyper, Dennis J. Schulte, Linda Trucks, Sven Azzaoui, Kamal Blommers, Marcel J. J. Gadiya, Yojana Karki, Reagon Zaliani, Andrea Gribbon, Philip da Silva Almeida, Marcius Dinis Anobom, Cristiane Bula, Anna L. Bütikofer, Matthias Putinhon Caruso, Ícaro [UNESP] Caterina Felli, Isabella Da Poian, Andrea T. Cardoso de Amorim, Gisele Fourkiotis, Nikolaos K. Gallo, Angelo Ghosh, Dhiman Gomes-Neto, Francisco Gorbatyuk, Oksana Hao, Bing Kurauskas, Vilius Lecoq, Lauriane Li, Yunfeng Cunha Mebus-Antunes, Nathane Mompeán, Miguel Cristtina Neves-Martins, Thais Ninot-Pedrosa, Martí Pinheiro, Anderson S. Pontoriero, Letizia Pustovalova, Yulia Riek, Roland Robertson, Angus J. Jose Abi Saad, Marie Treviño, Miguel Á. Tsika, Aikaterini C. Almeida, Fabio C. L. Bax, Ad Henzler-Wildman, Katherine Hoch, Jeffrey C. Jaudzems, Kristaps Laurents, Douglas V. Orts, Julien Pierattelli, Roberta Spyroulias, Georgios A. Duchardt-Ferner, Elke Ferner, Jan Fürtig, Boris Hengesbach, Martin Löhr, Frank Qureshi, Nusrat Richter, Christian Saxena, Krishna Schlundt, Andreas Sreeramulu, Sridhar Wacker, Anna Weigand, Julia E. Wirmer-Bartoschek, Julia Wöhnert, Jens Schwalbe, Harald |
dc.subject.por.fl_str_mv |
COVID19-NMR Drug Discovery Fragment Screening NMR Spectroscopy Protein SARS-CoV-2 |
topic |
COVID19-NMR Drug Discovery Fragment Screening NMR Spectroscopy Protein SARS-CoV-2 |
description |
SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-11-14 2023-07-29T12:30:39Z 2023-07-29T12:30:39Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1002/anie.202205858 Angewandte Chemie - International Edition, v. 61, n. 46, 2022. 1521-3773 1433-7851 http://hdl.handle.net/11449/246060 10.1002/anie.202205858 2-s2.0-85139756352 |
url |
http://dx.doi.org/10.1002/anie.202205858 http://hdl.handle.net/11449/246060 |
identifier_str_mv |
Angewandte Chemie - International Edition, v. 61, n. 46, 2022. 1521-3773 1433-7851 10.1002/anie.202205858 2-s2.0-85139756352 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Angewandte Chemie - International Edition |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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