17 Mar Anti-Folate Drugs Might Prevent COVID-19 (and other viruses) From Taking Over Cell Metabolism
MedicalResearch.com Interview with:
Benjamin E. Gewurz MD, PhD
Broad Institute of MIT and Harvard, Cambridge,
Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital,
Department of Microbiology, Harvard Medical School
MedicalResearch.com: What is the background for this study?
Response: When the Covid-19 virus infects cells, it takes over and redirects our cells resources towards the projection of virus building blocks and new viruses. Building blocks include large amounts of RNAs that encode for the viral proteins, much as the mRNA vaccines direct our bodies to make the spike protein. We wondered how the virus changes cell metabolism in order to support the synthesis of vast amounts of viral RNAs within hours of infection.
MedicalResearch.com: What are the main findings?
Response: We identified that SARS-CoV-2 coronavirus that causes COVID19 increases the ability of infected cells to synthesize nucleotide building blocks that can be used for viral RNA synthesis. Activity of a folate metabolism pathway normally used by our cells to make DNA and RNA nucleotides becomes more active. Based on this observation, we tested whether antifolate drugs, including methotrexate could suppress the production of coronavirus mRNA, protein and new viruses. In our cell culture model, we found that methotrexate, as well as another antifolate drug with a similar mechanism, each significantly suppressed the production of coronavirus proteins and viruses. The drugs also rescued infected cell from the toxic effects of virus replication
MedicalResearch.com: How can this research be used to develop medications to treat or possibly prevent disease?
Response: We continue to lack oral treatments that can be taken prophylactically or early after coronavirus infections. We are interested in testing these types of drugs, including orally dosed methotrexate, to test whether either can ameliorate covid-19 in animal models. It will be important to determine in these models how antifolates affect viral replication as well as immune responses to coronavirus infection. The idea of directing antiviral therapies at a host cell target is appealing, because it may be used in strategies to limit the evolution of viral resistance, perhaps in combination with other antiviral drugs. Because many types of viruses require a large supply of DNA or RNA for their lifecycles, it is possible that folate metabolism antagonists may have antiviral activity against a number of viruses. There is already some support for this idea in the medical literature, but more studies are needed to determine how they affect immune cells that also use folate metabolism.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: We are interested in testing methotrexate in animal models of COVID19, to study their effects on viral replication and on antiviral immune responses in vivo.
I would also like to mention that we have witnessed the emergence of three highly pathogenic coronaviruses over the past two decades: SARS, MERS and now SARS-CoV-2/COVID19. It is important to start working on treatments that could be effective against a future coronavirus that has yet to emerge. Since we don’t know which one this could turn out to be, it will be important to develop antiviral therapies that broadly target coronavirus replication. Directing therapies at host cell targets important for coronavirus replication is one approach to have in the armamentarium.
Any disclosures? Ben Gewurz and co-author Vamsi Mootha are listed as inventors on a patent application filed by the Broad Institute based on results from this manuscript. Vamsi Mootha is on the scientific advisory board and receives compensation from Janssen Pharmaceuticals and 5am Ventures and owns equity in Raze Therapeutics. B.E.G. receives research support from Abbvie, but that did not support this study.
Zhang, Y., Guo, R., Kim, S.H. et al. SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication. Nat Commun12, 1676 (2021). https://doi.org/10.1038/s41467-021-21903-z
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