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Vanderbilt biochemist Yi Ren is part of a team that has identified a new behavior of a SARS-CoV-2 protein and discovered that interfering with its function can block virus replication in host cells. This opens up the potential for new therapeutic targets for COVID-19.
The article, “Nsp1 Protein of SARS-CoV-2 Disrupts the mRNA Export Machinery to Inhibit Host Gene Expression,” was published in the journal Science Advances on Feb. 5.
A 2019 study conducted by Ren showed NS1 protein, a component that affects the severity of influenza A virus, targets the host NXF1 protein. NXF1’s primary function is to provide the signal for messenger RNA to enter the cytoplasm so it can be translated into protein. Since the start of the COVID-19 pandemic, Ren has been applying her expertise in the mechanisms of gene expression and viral proteins to better understand SARS-CoV-2.
The researchers acted quickly in early 2020, discovering that SARS-CoV-2 behaves like influenza A in mRNA signaling. “We identified an interaction between the virulence Nsp1 protein of SARS-CoV-2 and the host NXF1 protein—which we studied for the influenza A virus,” said Ren, assistant professor of biochemistry and Dean’s Faculty Fellow. “Because we were very familiar with NXF1, we could validate that this virus-host interaction has a similar outcome in SARS-CoV-2.”
Ren and her collaborators have also found that overexpression of NXF1 blocks viral infection of human cells. This could mean that inhibiting Nsp1 function will enable infected cells to express the genes that attack the virus, Ren explains. Within her lab and the Center for Structural Biology, Ren is working to understand in atomic detail how Nsp1 targets its host factor. With this information, other researchers will have a strong foundation from which to consider structure-based drug design.
In principle, this work is helpful in the study of future viruses. Viruses are very talented, Ren explains, because they can exploit the same pathway to a host cell through very different mechanisms. Learning more about each virus’ behavior can encourage more rapid development of targeted therapeutics.
The research was supported by the National Institutes of Health, the Canadian Institutes of Health Research, the Center for Research on Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases-funded Center of Excellence for Influenza Research and Surveillance, the Defense Advanced Research Projects Agency and others.