DHFR Inhibitors Display a Pleiotropic Anti-viral Activity Against SARS-CoV-2: Insights Into the Mechanisms of Action

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 R. Beccari; Arnaldo Caruso; Marcello Allegretti

doi:10.20944/preprints202304.0082.v1

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preprints.org > biology and life sciences > virology > doi: 10.20944/preprints202304.0082.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

DHFR Inhibitors Display a Pleiotropic Anti-viral Activity Against SARS-CoV-2: Insights Into the Mechanisms of Action

Version 1 : Received: 5 April 2023 / Approved: 6 April 2023 / Online: 6 April 2023 (09:21:51 CEST)

A peer-reviewed article of this Preprint also exists.

Iaconis, D.; Caccuri, F.; Manelfi, C.; Talarico, C.; Bugatti, A.; Filippini, F.; Zani, A.; Novelli, R.; Kuzikov, M.; Ellinger, B.; Gribbon, P.; Riecken, K.; Esposito, F.; Corona, A.; Tramontano, E.; Beccari, A.R.; Caruso, A.; Allegretti, M. DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action. Viruses 2023, 15, 1128. Iaconis, D.; Caccuri, F.; Manelfi, C.; Talarico, C.; Bugatti, A.; Filippini, F.; Zani, A.; Novelli, R.; Kuzikov, M.; Ellinger, B.; Gribbon, P.; Riecken, K.; Esposito, F.; Corona, A.; Tramontano, E.; Beccari, A.R.; Caruso, A.; Allegretti, M. DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action. Viruses 2023, 15, 1128.

Abstract

During COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Basing 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 associated to the intrinsic antimetabolic activity of these drugs, but also to a specific antiviral 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.

Keywords

COVID-19; drug repurposing; methotrexate; EXSCALATE; virtual screening; molecular docking; antiviral activity; SARS-CoV-2; viral entry; nsp13

Subject

Biology and Life Sciences, Virology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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