MILWAUKEE – Startling, never-before-seen images show that the new coronavirus hijacks proteins in our cells to create monstrous tentacles that branch out and may transmit infection to neighboring cells.
The finding, accompanied by evidence of potentially more effective drugs against COVID-19, published Saturday in the journal Cell by an international team of scientists.
By focusing on the fundamental behavior of the virus — how it hijacks key human proteins and uses them to benefit itself and harm us — the team was able to identify a family of existing drugs called kinase inhibitors that appear to offer the most effective treatment yet for COVID-19.
"We've tested a number of these kinase inhibitors and some are better than remdesivir," said Nevan Krogan, one of more than 70 authors of the new paper, and director of the Quantitative Biosciences Institute at the University of California, San Francisco.
While remdesivir has yet to be approved for use against COVID-19, U.S. regulators are allowing "emergency use" of the drug in hospitalized patients.
Krogan said tests of kinase inhibitors showed some, including Gilteritnib and Ralimetinib, required lower concentrations than remdesivir in order to kill off 50% of the virus.
The new study, which involved experiments using cells from humans and others from African green monkeys, shows that the virus known as SARS-CoV-2 is especially adept at disrupting vital communications. These communications take place both within cells and from one cell to another.
"This paper shows just how completely the virus is able to rewire all of the signals going on inside the cell. That's really remarkable and it's something that occurs very rapidly (as soon as two hours after cells are infected)," said Andrew Mehle, an associate professor of medical microbiology and immunology at the University of Wisconsin-Madison.
The communications system known as cell signaling, allows cells to grow, and to detect and respond to outside threats. Errors in cell signaling can lead to such illnesses as cancer and diabetes.
Mehle, who was not involved in the study, said the work shows that scientists are contending with a daunting enemy in the new conronavirus. "These are highly efficient, evolutionarily-tuned machines that will make it very challenging to develop therapeutics," he said.
A different approach
From early in the pandemic, Krogan and his colleagues have taken a different approach from that of many researchers seeking treatments for the new virus.
Many scientists have been screening thousands of drugs already approved for other uses to determine if they can also be used to treat COVID-19.
"We're not doing that," Krogan said. "We're saying 'Let's understand the underlying biology behind how the virus infects us, and let's use that against the virus.' "
In the search for treatments, many scientists have homed in on key proteins in the virus — especially the Spike protein, which allows the viral cells to attach themselves to human cells.
Krogan and his team looked in the opposite direction, focusing on the human proteins, instead of those in the virus. Dozens of human proteins play a critical role in the disease process because the virus needs them to infect people and to make copies of itself.
There is an important advantage to developing treatments aimed at the human, rather than the viral, proteins. Viral proteins can mutate causing them to develop resistance to the drugs targeted to them. Human proteins are far less likely to mutate.
In April, Krogan and his colleagues published a study in the journal Nature showing that 332 human proteins interact with 27 viral proteins.
Feixiong Cheng, a PhD researcher who runs a lab at Cleveland Clinic Genomic Medicine Institute, called the mapping of interactions between these proteins "a novel" and "powerful" strategy for finding existing drugs that might help COVID-19 patients.
In the new study, Krogan's international team looked deeper into the biology, focusing on how the new coronavirus changes a complex process called phosphorylation. This process acts as a series of on-off switches for different cell activities, including growth, division, death and communication with one another.
"What they've done is really a fantastic next step," said Lynne Cassimeris, a professor of biological sciences at Lehigh University, explaining that the work builds on the previous paper and applies knowledge of cell biology gained over the last 30 years.
"It's an amazing leap. We know that the virus has to be manipulating these human proteins. Now we have a list of what is changing over time."
Cassimeris said that mapping these changes allows researchers to seek drugs that can intervene at specific points.
The scientists found that on-off switches changed significantly in 40 of the 332 proteins that interact with the new coronavirus.
The changes occur because the virus either dials up or down 49 enzymes called kinases. The dialing up or down of kinases cause them to alter 40 of the proteins that interact with virus.
Imagine the kinases as guards protecting our health until the new coronavirus turns them against us. In each case, however, the new study identified treatments that can stop the virus from turning guards into assailants.
The virus most powerfully hijacks a kinase called CK2, which plays a key role in the basic frame of the cell as well as its growth, proliferation and death.
This led the scientists to investigate a drug called Silmitasertib. Tests found this drug inhibits CK2 and eliminates the new coronavirus.
They also found that the virus has a dramatic effect on a pathway — a group of kinases that form a cascade a little like falling dominoes. The virus hijacks this cascade so that the end result becomes a dangerous overreaction by our immune system.
The study's finding on this pathway may help to explain the extreme overreaction — a cytokine storm — that causes the immune system to kill both healthy and diseased tissue, leading to more than half of the deaths from COVID-19.
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Here too, the scientists were able to identify treatments, including the experimental cancer drug Ralimetinib, which may prevent the immune system overreaction.
Authors of the new study also found that the virus harms a family of kinases called CDKs. These play roles in cell growth and in the response to DNA damage. An experimental drug called Dinaciclib may be effective in thwarting this viral assault.
Finally, Krogan and his colleagues found that the virus also hijack a kinase that helps cells stay healthy in different environments and cleans out damaged cells. A small molecule called Apilimod targets this kinase and has been able to hinder the virus in lab tests.
Krogan, who is also an investigator at the Gladstone Institutes at UCSF, said the strategy of examining the human kinases affected by the virus has proved fruitful.
"The kinases are a very druggable set of proteins in our cells," he said.
Follow Mark Johnson on Twitter: @majohnso