Most antivirals used today target parts of an invasive virus itself. Unfortunately, SARS-CoV-2 – the virus that causes COVID-19 – has proven difficult to kill. But viruses rely on the cellular mechanisms of human cells to help them spread, so it should be possible to modify an aspect of a person’s body to prevent this, and to slow the virus down enough to allow the immune system to fight. the invader.
I am a quantitative biologist and my lab build a map of how coronavirus uses human cells. We used this card to find existing drugs that could be reused to fight COVID-19 and worked with an international group of researchers called QBI Coronavirus Research Group to see if the drugs that we have identified showed any promise. Many have.
For years, researchers have suspected that kinases – biological control switches that viruses use to take control of cells – could be targeted to fight infections. In recent months, we have built a second, more detailed map, specifically looking for kinases that the coronavirus hijacks.
Using this map, we identified some already existing anticancer drugs that alter the function of kinases that SARS-CoV-2 hijacks, and began testing them in cells infected with coronaviruses. the results of these first tests are promising enough for us to work with certain groups and have already started clinical trials on humans.
Kinases in disease and as drug targets
Kinases are proteins found in every cell in our body. There is 518 human kinases, and they act as major control centers for virtually every process in the body. They are able to add a small marker – a process called phosphorylation – to other proteins and thus change how, if and when a phosphorylated protein can do its job.
For example, if a cell is preparing to grow – say to heal a cut on your finger – the specific kinases will turn on and start telling proteins involved in cell growth what to do. Many cancers are caused by overactive kinases causing uncontrolled cell growth, and drugs that slow down kinases can be very effective in treating cancer.
Kinases are central actors in cell function as well as in most diseases, researchers and pharmaceutical companies have studied them in detail.
Kinases are also fairly easy to target with drugs how they add phosphorylation markers to proteins. Researchers have developed a large number of drugs, especially cancer drugs, which work primarily by throwing a key into the mechanics of specific kinases to stop cell growth.
So what does this have to do with coronavirus? Well, viruses and cancer actually have more in common than you might think. Cancer is essentially a cellular machinery dysfunction which causes uncontrolled cell growth.
Viruses also modify the function of cellular machinery – albeit intentionally – but instead of causing cell growth, the machinery is reused to produce more viruses. Without surprise, viruses take control on many kinases to do this.
Coronavirus at the controls
This idea – that SARS-CoV-2 uses kinases to hijack cellular machinery – is why we wanted to build a map of each kinase that is supported by the coronavirus. Any virus-kinase interaction could be a potential target for drugs.
To do this, we first infected green monkey cells – which are good substitutes for human cells regarding virus infection – with SARS-CoV-2. We then shredded these infected cells and used a device called mass spectrometer to see what proteins have been phosphorylated in these infected cells. We then did the same thing with healthy cells.
It is impossible to actually see which kinases are activated at all times, but as each kinase can attach phosphorylation markers to only a few specific proteins, researchers can examine phosphorylated proteins to determine which kinases are active at any time.
We made two lists: a list of phosphorylated proteins in healthy cells and a list of phosphorylated proteins in infected cells. We then compared the two, and looking at the differences between the infected and uninfected lists, we were able to determine which kinases the coronavirus uses to reproduce.
Because researchers don’t really understand what human 518 kinases do, we could only look for effects in 97 of the best known. But that turned out to be more than enough. Of these 97 kinases, we found 49 that the virus affects.
Some of the most interesting include Casein Kinase 2, which helps control the shape of a cell. We have also identified several kinases that work together in what is called the Signaling channel p38 / MAPK. This pathway reacts and controls the inflammatory reaction of our body. These kinases may be involved in the cytokine storm – an over-reaction of the dangerous immune system – which some patients with severe COVID-19 experience.
While identifying the kinases involved in the replication of SARS-CoV-2, we were also able to learn a lot about how the virus modifies our bodies. For example, CK2 becomes much more active during infection with a coronavirus and causes the growth of small tubes that extend from the surface of the cell. Under the microscope, it seems that the cell has full hair. We think SARS-CoV-2 could use these long cell growths – called filopod – as viral highways to bring the new viruses closer to neighboring cells, thus facilitating infection.
Kinase inhibitors in laboratory and clinical trials
Knowing more about the function of the virus is interesting for a biologist like me and could be useful down the road, but the ultimate goal of our project was to find drugs to treat COVID-19.
Once we knew what kinases SARS-CoV-2 uses to replicate and the proteins they change, we looked at database of approximately 250 kinase inhibitor drugs to see if any of them targeted the kinases used by the virus. To increase our chances, we also looked for drugs that hit some of the proteins that act on kinases. And of course, we found some.
There are 87 existing drugs that modify the kinase-controlled pathways used by the coronavirus. Most of these drugs are already approved for human use or are currently undergoing clinical trials to treat cancer, and could be readily reused to treat COVID-19 patients.
With these tracks, our collaborators New York and Paris tested the effect of 68 of these drugs on cells infected with SARS-CoV-2. Several of them have successfully killed the virus in cells. A few that are of particular interest to us – silmitasertib, gilteritinib, ralimetinib, apilimod and dinaciclib – are approved for treatment, clinical trials or preclinical development for various diseases.
Silmitasertib stops casein kinase 2, the kinase that causes cells to grow by the virus that spreads the filopod tubes. As soon as the company that made silmitasertib heard this news, it announced that it wanted to test the drug against COVID-19 in the clinic.
The drugs hitting the kinase pathways have been on researchers’ radar as potential potent antivirals for years, but none have paid off. By examining this new area of drug applications and using our new mapping approach, our team has added dozens of drugs to the growing list of potential tools to help fight this pandemic.
It is still too early to say if any of these drugs will work to treat COVID-19 in patients, but the more likely we are, the better.
[[[[In-depth knowledge, on a daily basis. Subscribe to The Conversation newsletter.]
This article is republished from The conversation, a non-profit news site dedicated to sharing ideas from academic experts.
Nevan Krogan receives funding from NIH, DARPA and Roche Pharmaceuticals.