Metabolic Pathways Used by SARS-CoV-2 to Replicate in Host Cells Identified

Researchers from Brigham and Women's Hospital, Massachusetts General Hospital (MGH), and the Broad Institute, have gained insight into the metabolic pathways co-opted by the SARS-CoV-2. The findings, published in Nature Communications, highlight the potential therapeutic benefit of drugs that inhibit folate and one-carbon metabolic pathways appropriated by the virus.

To identify which metabolic pathways to target, the researchers obtained samples of the virus and cultivated them. They then applied mass spectrometry approaches to identify the resources being consumed and produced by healthy cells and infected cells. They studied the infected cells eight hours after infection, when the virus had begun manufacturing its RNA and proteins but had not yet exerted a serious effect on host cell growth and survival.

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. Their study also found that it could offer a synergistic effect when administered with the antiviral drug Remdesivir. 

"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," corresponding author Benjamin Gewurz said. "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."