DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action

  • Daniela Iaconis (Shared first author)
  • Francesca Caccuri (Shared first author)
  • 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

Abstract

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.

Bibliographical data

Original languageEnglish
Article number1128
ISSN1999-4915
DOIs
Publication statusPublished - 09.05.2023
PubMed 37243214