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  The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models

Stegmann, K. M., Dickmanns, A., Gerber, S., Nikolova, V., Klemke, L., Manzini, V., et al. (2021). The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models. Virus Research, 302: 198469. doi:10.1016/j.virusres.2021.198469.

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Stegmann, K. M., Author
Dickmanns, A., Author
Gerber, S., Author
Nikolova, V., Author
Klemke, L., Author
Manzini, V., Author
Schlösser, D., Author
Bierwirth, C., Author
Freund, J., Author
Sitte, M., Author
Lugert, R., Author
Salinas, G., Author
Meister, T. L., Author
Pfaender, S., Author
Görlich, D.1, Author              
Wollnik, B., Author
Groß, U., Author
Dobbelstein, M., Author
Affiliations:
1Department of Cellular Logistics, MPI for biophysical chemistry, Max Planck Society, ou_578574              

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Free keywords: Coronavirus; SARS-CoV-2; COVID-19; Methotrexate; Folic acid; Dihydrofolate reductase; Leucovorin; Folinic acid; Inosine; Remdesivir; Purine synthesis; RNA replication; Spike; Nucleocapsid
 Abstract: The search for successful therapies of infections with the coronavirus SARS-CoV-2 is ongoing. We tested inhibition of host cell nucleotide synthesis as a promising strategy to decrease the replication of SARS-CoV-2-RNA, thus diminishing the formation of virus progeny. Methotrexate (MTX) is an established drug for cancer therapy and to induce immunosuppression. The drug inhibits dihydrofolate reductase and other enzymes required for the synthesis of nucleotides. Strikingly, the replication of SARS-CoV-2 was inhibited by MTX in therapeutic concentrations around 1 µM, leading to more than 1000-fold reductions in virus progeny in Vero C1008 (Vero E6) and ~100-fold reductions in Calu-3 cells. Virus replication was more sensitive to equivalent concentrations of MTX than of the established antiviral agent remdesivir. MTX strongly diminished the synthesis of viral structural proteins and the amount of released virus RNA. Virus replication and protein synthesis were rescued by folinic acid (leucovorin) and also by inosine, indicating that purine depletion is the principal mechanism that allows MTX to reduce virus RNA synthesis. The combination of MTX with remdesivir led to synergistic impairment of virus replication, even at 100 nM MTX. The use of MTX in treating SARS-CoV-2 infections still awaits further evaluation regarding toxicity and efficacy in infected organisms, rather than cultured cells. Within the frame of these caveats, however, our results raise the perspective of a two-fold benefit from repurposing MTX for treating COVID-19. Firstly, its previously known ability to reduce aberrant inflammatory responses might dampen respiratory distress. In addition, its direct antiviral activity described here would limit the dissemination of the virus.

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Language(s): eng - English
 Dates: 2021-06-062021-09
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.virusres.2021.198469
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Title: Virus Research
Source Genre: Journal
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Pages: - Volume / Issue: 302 Sequence Number: 198469 Start / End Page: - Identifier: -