Researchers at the University of Liverpool SARS-CoV-2 Viral proteases describe how to attack and target host cells to stop viral replication in cell cultures using currently clinically used drugs or drugs in the pipeline.
New findings published today (September 21, 2021) Nature CommunicationsIt provides a powerful resource for understanding proteolysis in the context of viral infections and for informing the development of targeted strategies for inhibiting the virus that causes Covid-19.
SARS-CoV-2 causes more than 227 million infectious diseases and more than 4.6 million deaths worldwide during a pandemic. Virus testing, treatment, and vaccination efforts all benefit from a better understanding of the basic biology of SARS-CoV-2.
Both viral and cellular proteases play important roles in SARS-CoV-2 replication, and protease-targeted inhibitors have already been successful in inhibiting SARS-CoV-2 in cell culture models. increase.
In this study, led by the University of Liverpool and the Pasteur Institute in Paris, researchers used a mass analysis approach to study proteolytic cleavage events during SARS-CoV-2 infection.
“Although mass analysis-based approaches to identify protease substrates have existed for many years, their application to the study of viral substrates is limited and to study proteolysis during coronavirus infection. It hasn’t been applied before, “explains Reed. Author Dr. Emot Edward, Tenure Track Fellow, Institute for Systems, Molecular and Integrated Biology, University.
The team discovered previously unknown cleavage sites in multiple viral proteins, including the major antigenic proteins S and N, which are the main targets of vaccine and antibody testing work.
They found a significant increase in cell cleavage events consistent with cleavage by SARS-CoV-2 main protease (Mpro), identified 14 potential reliable substrates for main and papain-like proteases, and identified a subset. I verified it. In vitro Assay.
They also found that siRNA depletion of these cellular proteins inhibited SARS-CoV-2 replication, and drugs targeting two of these proteins (tyrosine kinase SRC and Ser / Thr kinase MYLK) were dose-dependent for SARSCoV-. Showed that it showed a typical decrease. 2 Titor.
SARS-CoV-2 at concentrations where both bafetinib (an experimental cancer treatment) and sorafenib (an approved drug used to treat kidney and liver cancer) do not cause cytotoxicity in a human cell line model of infection. Showed inhibition.
Dr. Emot said: “A better understanding of the exact methods by which proteolytic cleavage is regulated, protein activity is regulated, and viral replication is useful is important for targeting the cellular matrix of viral proteases as a therapeutic strategy.
“Furthermore, as SARS-CoV-2 mutants emerge, we will incorporate post-translational modification data from such studies to support efforts to predict phenotypes from the genetic data of new mutants. You can also. “
Reference: “Characteristics of proteolysis during SARS-CoV-2 infection identify potentially therapeutic viral cleavage sites and cell targets” Bjoern Meyer, Jeanne Chiaravalli, Stacy Gellenoncourt, Philip Brownridge, Dominic P. Bryne, Leonard A. Daly, Arturas Grauslys, Marius Walter, Fabrice Agou, Lisa A. Chakrabarti, Charles S. Craik, Claire E. Eyers, Patrick A. Eyers, Yann Gambin, Andrew R. Jones, Emma Sierecki, Eric Verdin, Marco Vignuzzi , Edward Emmott, September 21, 2021 Nature Communications..
DOI: 10.1038 / s41467-021-25796-w
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