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 Rosario Beccari,
Arnaldo Caruso,
Marcello Allegretti
Affiliations
Daniela Iaconis
EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, Italy
Francesca Caccuri
Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Candida Manelfi
EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, Italy
Carmine Talarico
EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, Italy
Antonella Bugatti
Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Federica Filippini
Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Alberto Zani
Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Rubina Novelli
Dompè Famaceutici SpA, Via Campo di Pile snc, 67100 L’Aquila, Italy
Maria Kuzikov
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany
Bernhard Ellinger
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany
Philip Gribbon
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany
Kristoffer Riecken
Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Francesca Esposito
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), Italy
Angela Corona
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), Italy
Enzo Tramontano
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), Italy
Andrea Rosario Beccari
EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, Italy
Arnaldo Caruso
Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Marcello Allegretti
Dompè Famaceutici SpA, Via Campo di Pile snc, 67100 L’Aquila, Italy
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.
