DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action
During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds s...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/15/5/1128 |
| _version_ | 1797598109372514304 |
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| author | Daniela Iaconis Francesca Caccuri Candida Manelfi Carmine Talarico Antonella Bugatti Federica Filippini Alberto Zani Rubina Novelli Maria Kuzikov Bernhard Ellinger Philip Gribbon Kristoffer Riecken Francesca Esposito Angela Corona Enzo Tramontano Andrea Rosario Beccari Arnaldo Caruso Marcello Allegretti |
| author_facet | Daniela Iaconis Francesca Caccuri Candida Manelfi Carmine Talarico Antonella Bugatti Federica Filippini Alberto Zani Rubina Novelli Maria Kuzikov Bernhard Ellinger Philip Gribbon Kristoffer Riecken Francesca Esposito Angela Corona Enzo Tramontano Andrea Rosario Beccari Arnaldo Caruso Marcello Allegretti |
| author_sort | Daniela Iaconis |
| collection | DOAJ |
| description | During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs. |
| first_indexed | 2024-03-11T03:14:41Z |
| format | Article |
| id | doaj.art-b7bacb79c72b47389e3aeb9d63d3ca35 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T03:14:41Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-b7bacb79c72b47389e3aeb9d63d3ca352023-11-18T03:39:25ZengMDPI AGViruses1999-49152023-05-01155112810.3390/v15051128DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of ActionDaniela Iaconis0Francesca Caccuri1Candida Manelfi2Carmine Talarico3Antonella Bugatti4Federica Filippini5Alberto Zani6Rubina Novelli7Maria Kuzikov8Bernhard Ellinger9Philip Gribbon10Kristoffer Riecken11Francesca Esposito12Angela Corona13Enzo Tramontano14Andrea Rosario Beccari15Arnaldo Caruso16Marcello Allegretti17EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, ItalySection of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyEXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, ItalyEXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, ItalySection of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySection of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySection of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyDompè Famaceutici SpA, Via Campo di Pile snc, 67100 L’Aquila, ItalyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, GermanyResearch Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), ItalyDepartment of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), ItalyDepartment of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), ItalyEXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, ItalySection of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyDompè Famaceutici SpA, Via Campo di Pile snc, 67100 L’Aquila, ItalyDuring the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.https://www.mdpi.com/1999-4915/15/5/1128COVID-19drug repurposingmethotrexateEXSCALATEvirtual screeningmolecular docking |
| spellingShingle | Daniela Iaconis Francesca Caccuri Candida Manelfi Carmine Talarico Antonella Bugatti Federica Filippini Alberto Zani Rubina Novelli Maria Kuzikov Bernhard Ellinger Philip Gribbon Kristoffer Riecken Francesca Esposito Angela Corona Enzo Tramontano Andrea Rosario Beccari Arnaldo Caruso Marcello Allegretti DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action Viruses COVID-19 drug repurposing methotrexate EXSCALATE virtual screening molecular docking |
| title | DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action |
| title_full | DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action |
| title_fullStr | DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action |
| title_full_unstemmed | DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action |
| title_short | DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action |
| title_sort | dhfr inhibitors display a pleiotropic anti viral activity against sars cov 2 insights into the mechanisms of action |
| topic | COVID-19 drug repurposing methotrexate EXSCALATE virtual screening molecular docking |
| url | https://www.mdpi.com/1999-4915/15/5/1128 |
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