ArticleVirus research2021
The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models.
Article in Virus research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 49 citations in OpenAlex.
- Folic Acid and Endothelial Dysfunction in COVID-19.Life (Basel, Switzerland) · 2026Review
- Reprogramming Inflammatory Macrophages with Specialized Pro-Resolving Lipid Mediators: A Novel Immunotherapeutic Strategy for Asthma.Biomedicines · 2026Review
- MTHFR allele and one-carbon metabolic profile predict severity of COVID-19.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Targeting Monkeypox Virus Methyltransferase: Virtual Screening of Natural Compounds from Middle-Eastern Medicinal Plants.Molecular biotechnology · 2025Article
- Myricetin-bound crystal structure of the SARS-CoV-2 helicase NSP13 facilitates the discovery of novel natural inhibitors.Acta crystallographica. Section D, Structural biology · 2025Article
- Discovery of RNA-Protein Molecular Clamps Using Proteome-Wide Stability Assays.Journal of proteome research · 2025Article
- Discovery of RNA-Protein Molecular Clamps Using Proteome-Wide Stability Assays.bioRxiv : the preprint server for biology · 2024Article
- Interactions of SARS-CoV-2 with Human Target Cells-A Metabolic View.International journal of molecular sciences · 2024Review
- Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design.Nature communications · 2024Article
- Global Challenges After a Global Challenge: Lessons Learned from the COVID-19 Pandemic.Advances in experimental medicine and biology · 2024Article
- N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody.iScience · 2023Article
- The Impact of Metformin on the Development of Hypothyroidism and Cardiotoxicity Induced by Cyclophosphamide, Methotrexate, and Fluorouracil in Rats.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics.Molecular aspects of medicine · 2023Review
- DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action.Viruses · 2023Article
- Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities.Molecules (Basel, Switzerland) · 2022Review
- Article
- Combinational benefit of antihistamines and remdesivir for reducing SARS-CoV-2 replication and alleviating inflammation-induced lung injury in mice.Zoological research · 2022Article
- Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.Frontiers in immunology · 2022Article
- Remdesivir and Its Combination With Repurposed Drugs as COVID-19 Therapeutics.Frontiers in immunology · 2022Review
- Immunopathological events surrounding IL-6 and IFN-α: A bridge for anti-lupus erythematosus drugs used to treat COVID-19.International immunopharmacology · 2021Review
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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