Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease
The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2022.832431/full |
| _version_ | 1828355370520674304 |
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| author | Wiebke Ewert Sebastian Günther Francesca Miglioli Sven Falke Patrick Y. A. Reinke Stephan Niebling Christian Günther Huijong Han Vasundara Srinivasan Hévila Brognaro Julia Lieske Kristina Lorenzen Maria M. Garcia-Alai Christian Betzel Mauro Carcelli Winfried Hinrichs Dominga Rogolino Alke Meents |
| author_facet | Wiebke Ewert Sebastian Günther Francesca Miglioli Sven Falke Patrick Y. A. Reinke Stephan Niebling Christian Günther Huijong Han Vasundara Srinivasan Hévila Brognaro Julia Lieske Kristina Lorenzen Maria M. Garcia-Alai Christian Betzel Mauro Carcelli Winfried Hinrichs Dominga Rogolino Alke Meents |
| author_sort | Wiebke Ewert |
| collection | DOAJ |
| description | The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site. |
| first_indexed | 2024-04-14T02:41:15Z |
| format | Article |
| id | doaj.art-5abf90b91d214accbdd2fa885322f8ed |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-14T02:41:15Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-5abf90b91d214accbdd2fa885322f8ed2022-12-22T02:17:03ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462022-04-011010.3389/fchem.2022.832431832431Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like ProteaseWiebke Ewert0Sebastian Günther1Francesca Miglioli2Sven Falke3Patrick Y. A. Reinke4Stephan Niebling5Christian Günther6Huijong Han7Vasundara Srinivasan8Hévila Brognaro9Julia Lieske10Kristina Lorenzen11Maria M. Garcia-Alai12Christian Betzel13Mauro Carcelli14Winfried Hinrichs15Dominga Rogolino16Alke Meents17Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Hamburg, GermanyCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Hamburg, GermanyDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, ItalyCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Hamburg, GermanyCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Hamburg, GermanyEuropean Molecular Biology Laboratory Hamburg, DESY, Hamburg, GermanyEuropean Molecular Biology Laboratory Hamburg, DESY, Hamburg, GermanyEuropean XFEL GmbH, Schenefeld, GermanyInstitute of Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, University Hamburg, Hamburg, GermanyInstitute of Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, University Hamburg, Hamburg, GermanyCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Hamburg, GermanyEuropean XFEL GmbH, Schenefeld, GermanyEuropean Molecular Biology Laboratory Hamburg, DESY, Hamburg, GermanyInstitute of Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, University Hamburg, Hamburg, GermanyDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, ItalyInstitute of Biochemistry, University Greifswald, Greifswald, GermanyDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, ItalyCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Hamburg, GermanyThe papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site.https://www.frontiersin.org/articles/10.3389/fchem.2022.832431/fulldrug discoveryCOVID-19papain-like proteasex-ray crystallographydeubiquitinationSARS-CoV-2 |
| spellingShingle | Wiebke Ewert Sebastian Günther Francesca Miglioli Sven Falke Patrick Y. A. Reinke Stephan Niebling Christian Günther Huijong Han Vasundara Srinivasan Hévila Brognaro Julia Lieske Kristina Lorenzen Maria M. Garcia-Alai Christian Betzel Mauro Carcelli Winfried Hinrichs Dominga Rogolino Alke Meents Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease Frontiers in Chemistry drug discovery COVID-19 papain-like protease x-ray crystallography deubiquitination SARS-CoV-2 |
| title | Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease |
| title_full | Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease |
| title_fullStr | Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease |
| title_full_unstemmed | Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease |
| title_short | Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease |
| title_sort | hydrazones and thiosemicarbazones targeting protein protein interactions of sars cov 2 papain like protease |
| topic | drug discovery COVID-19 papain-like protease x-ray crystallography deubiquitination SARS-CoV-2 |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2022.832431/full |
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