Existing medications can prevent SARS-CoV-2 from hijacking cells

An international team of researchers has analyzed how SARS-CoV-2, the virus that causes COVID-19, hijacks proteins in their target cells. The research, published in the magazine. Cell, shows how the virus changes cell activity to promote its own replication and infect nearby cells. The scientists also identified seven clinically approved drugs that could alter these mechanisms, and recommend that these drugs be tested immediately in clinical trials.

The collaboration included researchers from the EMBL European Bioinformatics Institute (EMBL-EBI), the Coronavirus Research Group at the Institute for Quantitative Biological Sciences at the University of California, San Francisco School of Pharmacy (UCSF), the Howard Medical Institute Hughes, the Pasteur Institute and CIBSS Cluster Excellence at the University of Freiburg.

Viruses cannot replicate and spread on their own: they need an organism, their host, to transport, replicate, and transmit them to other hosts. To facilitate this process, viruses need to take control of the machinery of their host cell and manipulate it to produce new viral particles. Sometimes this sequestration interferes with the activity of the host’s enzymes and other proteins.

Once a protein is produced, enzymes can change their activity by making chemical modifications to its structure. For example, phosphorylation (the addition of a phosphoryl group to a protein by a type of enzyme called kinase) plays a critical role in regulating many cellular processes, including cell-to-cell communication, cell growth, and cell death. . By altering phosphorylation patterns in host proteins, a virus can potentially promote its own transmission to other cells, and eventually to other hosts.

The scientists used mass spectrometry, a tool to analyze the properties of a sample by measuring the mass of its molecules and molecular fragments, to evaluate all the host and viral proteins that showed changes in phosphorylation after SARS-CoV infection. two. They found that 12% of the host proteins that interact with the virus were modified. The researchers also identified the kinases that are most likely to regulate these modifications. Kinases are potential targets of drugs to stop virus activity and treat COVID-19.

The extraordinary behavior of infected cells.

“The virus prevents human cells from dividing, keeping them at a particular point in the cell cycle. This provides the virus with a relatively stable and suitable environment for further replication,” explains Pedro Beltrao, group leader at EMBL-EBI.

SARS-CoV-2 not only affects cell division, but also cell shape. One of the key findings of the study is that infected cells exhibit long, branched, arm-shaped or filopodia extensions. These structures can help the virus reach nearby cells in the body and advance infection, but further study is warranted.

“The clear visualization of the extensive branching of filopodia once again clarifies how understanding the biology of virus-host interaction can shed light on potential intervention points in disease,” says Nevan Krogan, director of the Institute for Quantitative Biosciences at UCSF and Principal Investigator at Gladstone Institutes.

Old drugs, new treatments

“The kinases possess certain structural characteristics that make them good pharmacological targets. Drugs have already been developed to attack some of the kinases that we identified, so we urge clinical researchers to test the antiviral effects of these drugs in their trials.” Beltrao says.

In some patients, COVID-19 causes an overreaction of the immune system, leading to inflammation. An ideal treatment would alleviate these exaggerated inflammatory symptoms while stopping virus replication. Existing drugs targeting kinase activity may be the solution to both problems.

The researchers identified dozens of drugs approved by the Food and Drug Administration (FDA) or ongoing clinical trials that target the kinases of interest. Seven of these compounds, primarily compounds against cancer and inflammatory diseases, demonstrated potent antiviral activity in laboratory experiments.

“Our data-driven approach to drug discovery has identified a new set of drugs that have great potential to combat COVID-19, either on their own or in combination with other drugs, and we are excited to see if they will help end this pandemic, “says Krogan.

“We hope to build on this work by testing many other kinase inhibitors while identifying the underlying pathways and potential additional therapies that can intervene in COVID-19 effectively,” says Kevan Shokat, professor in the UCSF Department of Cellular and Molecular Pharmacology.