Blocking Folate Metabolism with Oral, Prophylactic Drugs Could Reduce Viral Replication in SARS-CoV-2 Infected Cells

The findings highlight the potential therapeutic benefit of drugs such as methotrexate, which inhibit folate and one-carbon metabolic pathways appropriated by the virus.

When SARS-CoV-2, the virus that causes COVID-19, infects a human cell, it quickly begins to replicate by seizing the cell’s existing metabolic machinery. The infected cells churn out thousands of viral genomes and proteins while halting the production of their own resources. To identify which metabolic pathways to target, the researchers obtained samples of the virus and cultivated them in a highly protected facility called a BSL-3 laboratory.

In analyzing the amino acids and thousands of chemical metabolites produced by the cells, the researchers observed that infected cells had depleted stores of glucose and folate. They demonstrated that the SARS-CoV-2 virus diverts building blocks from glucose production to the assembly of purine bases, which are necessary for creating large amounts of viral RNA. Additionally, they found that the 1-carbon pathway used to metabolize folate was hyperactive, thus supplying the virus with more carbon groups for making bases for DNA and RNA.

Drugs that inhibit folate metabolism, like methotrexate, are often used to treat autoimmune conditions like arthritis and could be therapeutic candidates for COVID-19. Methotrexate is currently being assessed as a treatment for the inflammation that accompanies more advanced COVID-19 infections, but the researchers suggest that it could also be beneficial early on. Their study also found that it could offer a synergistic effect when administered with the anti-viral drug remdesivir. Methotrexate’s immune-suppressing properties could make its proper administration as a prophylactic challenging, however. Researchers would need to determine how to maximize the drug’s antiviral effects without significantly compromising a patient’s natural immune response. Still, the researchers have pointed out that oral antivirals are an important addition to an arsenal of therapies for COVID-19, serving both as an immediate treatment for infection as well as a defense against new variants and other coronaviruses.

“One of the things we’re lacking in this pandemic is a pill that can be taken orally, as a prophylactic agent, before someone is hospitalized or even before they’re infected,” said corresponding author Benjamin Gewurz, MD, PhD, of the Division of Infectious Diseases at the Brigham. “Monoclonal antibodies have a lot of promise but need to be given intravenously. Blocking the metabolism pathways that viruses rely on to replicate could be a new strategy for treating patients at an early timepoint.”

“We’re hoping that, ultimately, we can find a way of preventing viruses from using cells’ metabolism pathways to replicate themselves because that could limit the ability of viruses to evolve resistance,” added Gewurz. “We’re starting to see new viral variants, and we’re hoping that we can stay ahead of that - treating patients before the virus has the chance to make copies of itself that could become resistant to antibodies.”

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Brigham and Women’s Hospital
Massachusetts General Hospital
Broad Institute