Study offers insight into metabolic pathways ingested by SARS-CoV-2 for viral reproduction

When SARS-CoV-2, the virus that causes COVID-19, affects human cells, it rapidly begins to capture the existing metabolic machinery . The infectious cells secrete thousands of viral genomes and proteins while stopping the production of their own resources. Researchers from Brigham and Women’s Hospital, Massachusetts General Hospital (MGH), and the Broad Institute, studying cultured cells shortly after they contracted the virus, have now gained more insight into their metabolic pathways. -choose the virus.

The findings, published in Nature Communications, clarification of the potential therapeutic benefit of drugs such as methotrexate, which block the metabolic pathways of folate and monocarbons that are secreted by the virus.

One of the things we need in this pandemic is a pill that can be taken orally, as a prophylactic agent, before someone is hospitalized or even before they become infected. Monoclonal antibodies have many promise but they must be delivered internally. Blocking the metabolism pathways that viruses rely on reproducibility could be a new strategy for the early treatment of patients. “

Benjamin Gewurz, MD, PhD, Corresponding Author, Department of Infectious Diseases

To determine which metabolic pathways should be targeted, the researchers obtained samples of the virus and placed them in a large protected facility called the BSL-3 laboratory, located at the Broad Institute. They then teamed up with the laboratory of co-author Vamsi Mootha, MD, of MGH, to use large spectrometry techniques to identify the resources consumed and produced by healthy and infectious cells . They examined the infectious cells at an “eclipse point,” eight hours after infection, when the virus has begun to produce its RNA and proteins but has yet to adversely affect host cell growth and survival. .

In analyzing the amino acids and thousands of chemical metabolites produced by the cells, the researchers found that infectious cells had lost stores of glucose and folate. They showed that the SARS-CoV-2 virus removes building blocks from glucose production to the accumulation of purine substitutes, which are essential for the production of large amounts of viral RNA. In addition, they found that the 1-carbon pathway used to make folate metabolite was hyperactive, thus providing the virus with more carbon groups to make bases for DNA and RNA.

Drugs that inhibit folate metabolism, such as methotrexate, are often used to treat autoimmune conditions such as arthritis and may be therapeutic candidates for COVID-19. Methotrexate is currently being evaluated as a treatment for the inflammation that accompanies more advanced COVID-19 infections, but the researchers suggest that it may also be beneficial early on. Their study also found that it may offer a concomitant effect when administered with the anti-viral drug remdesivir. Proper administration of Methotrexate may have the prophylactic effect, however, by its protective properties. Researchers had to figure out how to counteract the antiviral effects of the drug without significantly affecting the patient’s natural immune response.

However, Gewurz reveals that oral antivirals are an important addition to an arsenal of treatments for COVID-19, serving both as an immediate treatment for infection as well as protection against new mutations and other coronaviruses. .

“We hope that, eventually, we can find a way to prevent viruses from using cell metabolism pathways to reproduce themselves as this could limit the ability of viruses to infect. growing up, “Gewurz said.” We’re starting to see new viral changes, and hopefully we can stay ahead of that – treating patients before the virus has a chance. make copies of yourself that may be resistant to antibodies. “