Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies
We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the l...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2289007 |
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| author | Zorana Ferjancic Filip Bihelovic Bojan Vulovic Radomir Matovic Milena Trmcic Aleksandar Jankovic Milos Pavlovic Filip Djurkovic Radivoje Prodanovic Aleksandra Djurdjevic Djelmas Nevena Kalicanin Mario Zlatovic Dusan Sladic Thomas Vallet Marco Vignuzzi Radomir N. Saicic |
| author_facet | Zorana Ferjancic Filip Bihelovic Bojan Vulovic Radomir Matovic Milena Trmcic Aleksandar Jankovic Milos Pavlovic Filip Djurkovic Radivoje Prodanovic Aleksandra Djurdjevic Djelmas Nevena Kalicanin Mario Zlatovic Dusan Sladic Thomas Vallet Marco Vignuzzi Radomir N. Saicic |
| author_sort | Zorana Ferjancic |
| collection | DOAJ |
| description | We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections. |
| format | Article |
| id | doaj-art-42b63272ecfc453f83c5a84edc1ae71b |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-42b63272ecfc453f83c5a84edc1ae71b2025-08-20T01:57:44ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2023.2289007Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studiesZorana Ferjancic0Filip Bihelovic1Bojan Vulovic2Radomir Matovic3Milena Trmcic4Aleksandar Jankovic5Milos Pavlovic6Filip Djurkovic7Radivoje Prodanovic8Aleksandra Djurdjevic Djelmas9Nevena Kalicanin10Mario Zlatovic11Dusan Sladic12Thomas Vallet13Marco Vignuzzi14Radomir N. Saicic15Faculty of Chemistry, University of Belgrade, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaUniversity of Belgrade-Institute of Chemistry, Technology and Metallurgy, Belgrade, SerbiaInnovation Centre of the Faculty of Chemistry, Belgrade, SerbiaUniversity of Belgrade-Institute of Chemistry, Technology and Metallurgy, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaUniversity of Belgrade-Institute of Chemistry, Technology and Metallurgy, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaInstitut Pasteur, Center for the Viral Populations and Pathogenesis, Paris, FranceInstitut Pasteur, Center for the Viral Populations and Pathogenesis, Paris, FranceFaculty of Chemistry, University of Belgrade, Belgrade, SerbiaWe developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.https://www.tandfonline.com/doi/10.1080/14756366.2023.2289007COVID-19antiviralsiminosugarshost-directed actionpandemic preparednessglycosidase inhibitors |
| spellingShingle | Zorana Ferjancic Filip Bihelovic Bojan Vulovic Radomir Matovic Milena Trmcic Aleksandar Jankovic Milos Pavlovic Filip Djurkovic Radivoje Prodanovic Aleksandra Djurdjevic Djelmas Nevena Kalicanin Mario Zlatovic Dusan Sladic Thomas Vallet Marco Vignuzzi Radomir N. Saicic Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies Journal of Enzyme Inhibition and Medicinal Chemistry COVID-19 antivirals iminosugars host-directed action pandemic preparedness glycosidase inhibitors |
| title | Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies |
| title_full | Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies |
| title_fullStr | Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies |
| title_full_unstemmed | Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies |
| title_short | Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies |
| title_sort | development of iminosugar based glycosidase inhibitors as drug candidates for sars cov 2 virus via molecular modelling and in vitro studies |
| topic | COVID-19 antivirals iminosugars host-directed action pandemic preparedness glycosidase inhibitors |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2289007 |
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