SARS-CoV-2 shutdown by drugs that block host cell signaling pathways

When SARS-CoV-2 infects a host cell, it effectively rewires the host cell. Thus, SARS-CoV-2 reverses the phosphoprotein switch in the host cell’s signal transduction circuit, ensuring that the host cell supports viral activities such as replication. It goes without saying that the infection involves rewiring. Hidden are details such as the ID of the switch to flip. Given these details, rewiring that maintains a SARS-CoV-2 infection could probably be reversed by drugs already approved for other purposes.

Scientists at the Goethe University and the University of Frankfurt Hospital have found that in order to understand host cell signaling and reveal drug targets (and potentially useful drugs), humans infected with SARS-CoV-2 can be exposed to phosphorylation. We studied ways to bring about oxidative-driven signal transduction changes. Scientists headed by Christian Münch University at Goethe University and Sindrich Sinattle Hospital at Frankfurt University used a comprehensive approach to whole-cell phosphorylation proteomics.

By identifying all proteins that retained a phosphate group at a particular moment, scientists have the opportunity to recognize proteins involved in cell signaling events behind SARS-CoV-2 infection. It was. In fact, scientists have found that growth factor receptor (GFR) signaling and downstream pathways are activated during SARS-CoV-2 infection.

You can read more about this discovery and its impact in the article (“Inhibition of growth factor receptor signaling interferes with SARS-CoV-2 replication“) Recently appeared Molecular cell.. In addition to identifying signaling pathways that could target COVID-19 therapy, this article pointed out that the pathways may be disrupted by existing drugs. Some such drugs, which happen to be anti-cancer agents, have been shown to be effective in a cellular model of COVID-19.

“Here, we identify changes in the cellular phosphoprotein network when infected with SARS-CoV-2 to gain insights into infection-induced signaling events,” the author of the article wrote. “We found extensive reorganization of cell signaling pathways, especially growth factor receptor (GFR) signaling.

“Surprisingly, inhibition of GFR signaling using prominent (anti-cancer) drugs (ie, pitilicib, omiparisib, RO5126766, lonafanib, sorafenib) interferes with SARS-CoV-2 replication in vitro and It was assessed by denaturing effects and viral RNA replication and release. These compounds prevented replication at clinically achievable concentrations.”

“Because these drugs are clinically available, we were able to move rapidly to clinical trials to test their feasibility as COVID-19 treatment options.”

Phosphate groups play important biochemical roles in the transmission of signals inside cells, either maintaining metabolism or stimulating molecular processes leading to activities such as cell proliferation. Phosphate groups bind to proteins or are removed to control activity. In this process, changes in proteins cause the following changes, and signals are transmitted in the signaling cascade. The target is usually the cell nucleus where genes are switched on or off.

By conducting a comprehensive study of phosphate group changes that occur during SARS-CoV-2 infection, scientists have identified which signaling pathways are involved. In addition, scientists can provide mechanistic basis for how signal-conditioned SARS-CoV-2 drugs work. Signal-modulated SARS-CoV-2 drug proposals are rarely available grounds when derived from bioinformatics analysis of genetics or cellular data.

“We can accurately block the growth factor signaling pathway at the point where extracellular signals dock to growth factor receptors, which are signal receivers,” says Münch. “But further down the cascade, there are some highly effective cancer therapeutics that interfere with growth factor signaling pathways, through which various growth factor receptor signals are blocked. Tested five of these substances in cells, and all five completely stopped SARS-CoV-2 replication.”

“We did experiments on cultured cells in the lab,” added Cinatl. “This means that the results cannot be transferred to humans without further testing. However, from testing with other infectious viruses, the viruses often alter the signal transduction pathways of human host cells.” It has been found that this is important for viral replication.At the same time, already approved drugs have a very large lead in terms of development, so the results and only a few experiments have Based on that, clinical trials can start very quickly.”