By 2020, the new crown virus (SARS-CoV-2) has infected more than 10 million people worldwide, killing more than half a million people. There is no doubt that we urgently need to develop effective antiviral therapies. In a new research paper published online in the leading academic journal Cell, an international team of researchers has identified a variety of compounds that inhibit viral activity by analyzing the specific processes of the neo-coronavirus “hijacking” cell proteins, which were previously unknown to them as having the potential to treat COVID-19. Given that some of them have been approved by the FDA, the researchers recommend testing these drugs in clinical trials as soon as possible.
The work is carried out by the European Molecular Biology Laboratory (EMBL), the University of California, San Francisco (UCSF), the Howard Hughes Institute of Medicine (HHMI), the Pasteur Institute in France, and the University of Freiburg in Germany.
In the face of this new virus, although in just six months, people have had many breakthroughs in understanding, however, we continue to use human cells to replicate and infect more cells process, there are many unknowns.
There is growing research evidence that the spread of the new coronavirus has different characteristics than other similar viruses. If more details can be found about the new crown virus-infected cells, more targeted strategies can be found to treat the new coronal disease. This is also the significance of this research work.
We know that viruses cannot replicate on their own and must rely on other organisms (i.e. hosts) to carry, replicate, and spread to new hosts. In the process, the virus needs to manipulate the protein machine sin of the host cell to produce new virus particles.
The researchers note that this process of “hijacking” host cells involves changes in the activity of a range of enzymes and other proteins. Phosphinization is an important way to regulate protein activity, playing a key role in cell growth and death, cell-to-cell signaling, and so on. Specifically, phosphorylation refers to an enzyme called kinase that adds a phosphate group to the target protein, changing the activity of the protein.
How does a virus change the phosphorylation patterns of proteins in cells to promote their own spread? To answer this, the team used mass spectrometry-based proteomics to assess cells infected with the new coronavirus and measure changes in host proteins and viral proteins. They found that 12 percent of the proteins in cells that interact with viruses have changed phosphorylation. Among them, the activation of casein kinase II (CK2) and p38/MAPK signaling pathways is most likely to regulate these modification processes. These results suggest that kinase is a potential drug target to stop the virus’s activity.
When cells infect the new coronavirus, the activity rises (red) and the tumor and its signaling pathways rise (red) and decrease (blue)
The study found that, by the interlocking effect of a series of kinases, the new coronavirus infection caused the cell to stay at a node in the cell cycle. This means that “the virus hinders cell division and provides a relatively stable and abundant environment for continuous replication of the virus.” Dr. Pedro Beltrao, head of the EMBL team, explained.
Even more surprising is that the new coronavirus not only affects cell division, but also allows infected cells to change shape, growing slender, forked filament-like feet that act like many of the “arms” that the cells stretch out to help the virus “reach” neighboring cells. The researchers speculate that structural changes in cells help infect more cells!
New coronavirus particles shown in cell filamented pseudo-foot
Based on the results of the kinase activity analysis, the researchers identified 87 drugs and compounds with antiviral potential. “The structural characteristics of kinase make them good drug targets. Professor Beltrao said, “There are already some drugs developed for the several kinases we have identified, so we think that clinical researchers can test the antiviral effects of these drugs in trials.” “
Among the drugs and compounds initially tested in the lab, the researchers found that seven of them, including targeted kinases such as silmitasertib, an anti-cancer drug in small molecules, and giteritinib, which has been approved for leukemia, showed strong antiviral activity in the experiment. “We hope to build on this work by testing more kinase inhibitors and identifying more mechanisms and potential therapies that can effectively intervene in COVID-19.” Professor Kevan Shokat, head of research at UCSF, said.
Professor Nevan Krogan, another co-author, said: “The data-driven drug discovery approach allows us to identify a new set of drugs that can be used alone or in combination with other drugs, with great potential to fight the new crown. If these drugs will end the outbreak, we will be happy. “
Expecting scientists’ efforts to bring the outbreak to an end as soon as possible is the biggest wish of countless people in the second half of 2020.