COVID-19 is a baby virus. It consists of only 29 proteins. Despite this, the coronavirus has already killed 80,000 people and put the whole world on a joke. Moreover, there are very few weaknesses that can be exploited. Atlantic writes about what scientists have already learned about the virus and how they plan to fight the new disease.
Twenty nine. This is the maximum amount of proteins in the arsenal of the new coronavirus to attack human cells. That is, 29 proteins versus tens of thousands of proteins that make up a much more complex and finely organized human body. 29 proteins that have captured enough cells in enough organisms to kill over 80,000 people and put the world on hold.
If it becomes possible to stop COVID-19 (with the help of a vaccine, treatment, drug), then this will be done by blocking such proteins so that they cannot capture, suppress and bypass the human cellular mechanism. The coronavirus, with its pitiful 29 proteins, may seem like a primitive little thing, but that's what makes it so hard to fight. He has very few weaknesses to exploit. By comparison, bacteria can contain hundreds of proteins.
Scientists are scrambling to find vulnerabilities for the SARS-CoV-2 coronavirus, which causes the COVID-19 disease, since it was found to have caused mysterious cases of pneumonia in Wuhan, China in January. In three short months, laboratories around the world were able to target individual proteins, calculating and drawing some of their structures atom by atom at record speed. Other researchers are examining the molecular libraries and blood of the recovered people, looking for substances that can firmly bind and suppress these viral proteins. More than 100 approved and experimental drugs are now being tested for their use against COVID-19. In mid-March, the first volunteer was injected with an experimental vaccine from the Moderna company.
And some researchers are testing how these 29 proteins interact with different parts of the human cell. The goal of research is to find drugs that attack the host, but not the virus. This seems like a long way from fighting a virus, but such searches allow you to track the replication cycle of the virus. Unlike bacteria, viruses cannot copy themselves. "The virus uses carrier mechanisms," says microbiologist Adolfo García-Sastre of the Icahn School of Medicine at Mount Sinai Medical Center. They trick the host's cells into copying their viral genomes and making their viral proteins.
One idea is to stop this kind of work started at the behest of the virus without interfering with the normal functioning of the cell. Here it is hardly possible to draw an analogy with an antibiotic to combat SARS-CoV-2, which kills foreign bacterial cells indiscriminately. “I think it's more like cancer therapy,” Kevan Shokat, a pharmacologist at the University of California, San Francisco, told me. In other words, we can talk about the selective destruction of human cells that have gone wild. This makes it possible to deal with additional targets, but this also raises a problem. It is much easier for a drug to tell the difference between a person and a bacterium than between a person and a person who has undergone a viral attack.
Thus, antiviral drugs rarely become the "miracle cure" that antibiotics are for fighting bacteria. The drug Tamiflu, for example, can reduce the duration of SARS by a day or two, but it cannot completely cure the disease. Drugs for HIV and hepatitis C must be mixed with two or three other drugs because the virus can quickly mutate and become resistant. The good news about SARS-CoV-2 is that it doesn't mutate very quickly by viral standards. In the course of the disease, you can choose other targets for treatment.
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Prevent the virus from entering the cell
Let's start with where the virus appears. The virus gets tricked into the host cell. SARS-CoV-2 is covered in spikes of lollipop-like proteins. The tips of these spines can bind to the ACE2 receptor, which is present in some human cells. It is because of these spike proteins that coronaviruses from the group including SARS-CoV-2, MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS (SARS virus) got their name - after all, they create a kind of crown. These three coronaviruses are so similar because of their spike proteins that scientists are using a strategy to treat MERS and SARS to combat SARS-CoV-2. Clinical trials of the vaccine from Moderna were able to start so quickly because they build on previous research on the MERS protein.
The spike protein is also the focus of antibody therapy. Such treatments can be developed faster than a new pill, because in this case the strength of the human immune system is involved. The immune system forces a protein compound called antibodies to neutralize foreign proteins such as those carried by a virus. Some American hospitals are trying to transfuse patients with antibody-rich plasma from those who have successfully contracted COVID-19. Nowadays, research teams and biotech companies are also testing the plasma of recovered people to determine antibodies that can be produced in large quantities in factories. The spike protein is a perfectly logical target for antibodies, because there is a lot of it outside the virus. Again, the similarities between SARS-CoV-2 and SARS are beneficial here."It's so similar to SARS that we got a head start and made a head start," says Program Manager Amy Jenkins of the Defense Advanced Research Projects Agency, which funds four different teams working on antibody therapies. for the treatment of COVID-19.
But the SARS-CoV-2 virus is not enough just to attach its spike protein to the receptor to get inside the cell. In fact, the spine is passive until it splits in two. The virus uses another human enzyme, say furin or TMPRSS2 (a dissonant name), which inadvertently activates the spike protein. Some experimental drugs are designed to prevent these enzymes from unintentionally doing the work of the virus. One possible mechanism for the hype of the malaria drug hydroxychloroquine, which Trump is fixated on, is precisely by suppressing the activity of the thorns.
When the spike protein is activated, SARS-CoV-2 fuses with the host cell membrane. He injects his genome and gets inside.
Interfere with the reproduction of the virus
To a human cell, the naked genome of SARS-CoV-2 appears to be a specific type of RNA, a molecule that usually gives instructions for making new proteins. Therefore, the human cell, being like a soldier who received a new order, obediently begins to produce new viral proteins, and new viruses appear.
Replication is a complex process that antiviral drugs can affect. "There are many, many proteins involved … and many potential targets are emerging," says virologist Melanie Ott, who works at Gladstone Research and at the University of California, San Francisco. For example, the experimental antiviral drug Remdesivir, which is undergoing clinical trials for its suitability for treating COVID-19, affects a viral protein that copies RNA, and then the process of genome copying is disrupted. Other viral protease proteins are needed to release viral proteins that are linked into one long strand so that they can detach and help the virus replicate itself. And some proteins help to modify the inner lining of the human cell,creating bubbles there that turn into small virus factories. “The replication mechanism sits on the envelope, and then suddenly starts producing tons of viral RNA, doing it over and over again,” Matthew Frieman, a virologist at the University of Maryland School of Medicine, told me.
In addition to the proteins that help the virus replicate itself, and the spike proteins that make up the outer capsule of the coronavirus, SARS-CoV-2 has a set of very mysterious "accessory proteins" that are unique and unique to this virus. If we understand what these accessory proteins are for, scientists can discover other ways SARS-CoV-2 interacts with the human cell, Freeman said. It is possible that accessory proteins help the virus somehow bypass the natural antiviral defense of the human cell. In this case, this is another potential target for the drug. "If you interrupt this process," Freeman said, "you can help the cell suppress the virus."
So that the immune system does not fail
Most likely, antiviral drugs are most effective in the early stages of infection, when the virus has infected few cells and made few copies of itself. “If antiviral drugs are given too late, the risk is that the immune component is already broken by this time,” Ott says. In the specific case of COVID-19, those patients who become seriously ill and incurably experience the so-called cytokine storm, when the disease triggers a violent and uncontrolled immune response. This is unnatural, but a cytokine storm can further affect the lungs, sometimes very seriously, as it causes fluid to accumulate in the tissues. Stephen Gottschalk, an immunologist at St. Jude Children's Research Hospital, talks about this. Thus,Another way to fight COVID-19 is by targeting the immune response, not the virus itself.
A cytokine storm does not only happen during COVID-19 and other infectious diseases. It is possible in patients with hereditary diseases, with autoimmune diseases, in those who have undergone bone marrow transplantation. Those drugs that calm the immune system in such patients are now being reoriented to fight COVID-19 through clinical trials. University of Alabama rheumatologist Randy Cron plans to conduct small trials of the immunosuppressant Anakinra, which is currently being used to treat rheumatoid arthritis. Other commercially available drugs such as tocilizumab and ruxolitinib, which were developed for the treatment of arthritis and bone marrow, are also being repurposed. Fighting a viral infection by suppressing the immune system is quite problematic,because the patient must be rid of the virus at the same time.
What's more, says Crohn, COVID-19 disease statistics indicate that the cytokine storm during this disease is unique, even when compared to other respiratory infections such as influenza. “It starts very quickly in the lungs,” says Krohn. But at the same time, it affects other organs less. The biomarkers of such a cytokine storm are not as "terribly" high as usual, although the lungs are severely affected. After all, COVID-19 and the virus that causes this disease are unknown to science.
Initial research to create drugs for COVID-19 is focused on repurposing existing drugs, because that way a patient in a hospital bed can get something faster. Doctors already know their side effects, and companies know how to produce them. But these repurposed drugs are unlikely to be a panacea for COVID-19, unless the researchers are incredibly lucky. However, these medications can help a patient with a mild form of the disease, preventing him from developing into a severe form. This will release one ventilator. “Over time, we will surely achieve great success, but for now we need something to start,” says Garcia-Sastre.
Sarah Zhang (SARAH ZHANG)