SARS-CoV-2 Protease Target Inhibition Could Stop Virus Replication

Researchers at the University of Liverpool and the Pasteur Institute in Paris, have shown how SARS-CoV-2 viral proteases attack the host cell, and how this can be targeted to stop virus replication in cell culture using existing drugs. The new findings, published today in Nature Communications, offer a powerful resource to understand proteolysis in the context of viral infection. 

In this study, researchers used a mass spectrometry approach to study proteolytic cleavage events during SARS-CoV-2 infection. “Mass spectrometry-based approaches to identify protease substrates have existed for a number of years however, they have seen only limited application to the study of viral substrates, and had not been previously applied to the study of proteolysis during coronavirus infection,” explains lead author Edward Emmott.

The team found previously unknown cleavage sites in multiple viral proteins, including major antigenic proteins S and N, which are the main targets for vaccine and antibody testing efforts. They discovered significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease (Mpro) and identified 14 potential high-confidence substrates of the main and papain-like proteases, validating a subset with in vitro assays. They went on to show that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, showed a dose-dependent reduction in SARS CoV-2 titers.

“As further SARS-CoV-2 variants emerge, the incorporation of post-translational modification data from studies such as this can also support efforts to predict phenotypes from genetic data on emerging variants,” Emmott concluded.