From every angle we are being bombarded with coronavirus-related information. Unfortunately, very little of what we hear has scientific justification. This is understandable, as everything is happening so quickly, the situation changes on a daily basis, journalists have to report and politicians try to pretend that they have the situation under control. Many of us are simply scared whilst hoping for a return to “normal life”. Let’s try to have a scientific look at the situation and our options going forward.
Viruses were and are always around, probably evolving together with us. From time to time we have been attacked by them in the past. But we have always won such wars, as we still exist as humans and dominate evolutionary development. Winning wars also means accepting casualties. There definitely have been. Probably the most recorded case so far was that of the so-called Spanish flu. The name we use for it today is actually quite interesting. The pandemic caused by the H1N1 influenza A virus actually started in the U.S. As it occurred during WWI, all information was censored so the public remained in the dark about it in order not to destroy the social morale which was crucial during the war. However, Spain was neutral during WWI and information about the virus outbreak was not censored, thus creating a false impression that the epidemiological situation was particularly serious there – which in fact was not true.
Spanish flu most likely started in the U.S. and was brought to Europe by American troops. We do not know for sure how COVID-19 started, but most likely it was transferred from animals. Regardless of its origin, it has had catastrophic consequences on the world’s population and economy. Its scale is fortunately not comparable compared with that of the Spanish flu. The reason for this may be a different virulence of the coronavirus, as well as the level of the healthcare and epidemiological knowledge at that time, as compared to nowadays.
Safety and preventive measures put in place in many countries, such as drastic reduction in social contacts and travel limitations, have clearly helped to control COVID-19 from spreading. With isolation alone the fight against coronavirus is not possible, as 100% of any large population will not fully obey government-imposed rules.
In conclusion, we need a vaccine which will help to build herd immunity and a fast-acting drug to enable sick patients to survive and recover.
The process of introducing a new drug to the market can take as long as ten years. Right now, we do not have such time. This is why the majority of organisations that are trying to find “the drug”, are looking to repurpose existing drugs and are examining drugs already in advanced stages of their development. Successful repurposing of existing drugs could save us a lot of time. As such several strategies are being considered.
Coronavirus uses a glycoprotein called Spike protein to bind to a receptor on the surface of cells, for example in humans. Binding allows cell entry, the first step of in host invasion. When viewed using a transmission electron microscope the spikes formed by Spike protein on the virus surface, look like a crown (corona in latin), this gives the name to this type of virus. An obvious strategy would be to block the Spike protein to disable cell penetration. It can be performed in a natural way, using antibodies found in serum from COVID-19 survivors. This method appears simple and it works but it is difficult to use on a large scale. This is why companies, including Takeda or Regeneron, are developing modified antibodies or cocktails of such, in order to enhance the therapeutic response.
Another strategy to prevent the virus from entering the cell is providing it with false binding sites. When attacking a cell, the virus binds to the angiotensin converting enzyme 2 (ACE2) receptor, present on the cell surface. ACE2 is found in several types of tissues (for example in the lung but also intestinal) in the human body and plays an important role in controlling blood pressure, but unfortunately it is also used by coronavirus as an entry point. A strategy tested by Apeiron using APN01 relies on providing recombinant soluble ACE2 receptor. Coronavirus binds to soluble ACE2 receptor rather than to the ACE2 receptor on the cell surface, resulting in reduced cell attack
Disruption of virus replication
If cell infection is not prevented viral replication is inevitable. One infected cell can produce hundreds or even thousands of viral copies which, when released from a cell, can invade neighbouring cells. Therefore, blocking replication is a promising strategy.
All coronaviruses use the same mechanism to replicate, which is based on RNA polymerase. It is both very efficient, yet also an erratic mechanism. RNA polymerase makes a lot of “mistakes” producing dysfunctional viral RNA copies. To avoid the “mistakes”, a correcting mechanism based on the action of exoribonuclease is employed.
Gilead’s Remdesivir (or rather its metabolite, since Remdesivir is a pro-drug) disrupts the correcting mechanism which leads to a reduction in viral replication. A similar mechanism by EIDD-2801, from Ridgeback Biotherapeutics, has been demonstrated. EIDD-2801 may be administered orally (unlike Remdesivir). Another benefit of EIDD-2801, is that it is active on mutated coronaviruses, which makes it a very promising therapy.
Therapies using other known antiviral drugs based on blocking RNA polymerase are also being tested. Favipiravir (developed by Toyama Chemical, approved in Japan in 2014 for treatment of novel types of influenza) was approved in Russia for COVID-19 treatment at the end of May 2020. Another example of known antiviral drugs being tested for treatment of COVID-19 is the Danoprevir-Ritonavir cocktail.
Reducing organism reaction
Organisms infected by a virus fight against it. In the majority of infected people, the immune system is capable to defend against a virus and prevent serious symptoms from developing. In some patients, unfortunately, fluid is produced in their lungs causing breathing difficulties and other lung disfunction which can lead to death. This are downstream effects of immune system over-activation. A key player in this process is IL-6 (interleukin-6). IL-6 is a cytokine responsible for inflammatory process regulation. Another type of anti-coronavirus therapy, is based on reducing the level of IL-6, thereby dampening the intensity of the organism’s inflammatory reaction allowing for a greater chance of survival. Genentech and Regeneron are using anti-IL-6 antibodies to achieve this. JAK inhibitors are also being tested as IL-6 reducing agents in severe coronavirus infections, for example, with Pfizer’s small molecule tofacitinib or Eli-Lily’s ruxolitinib and baricitinib.
To date there has never been such an intensive search for a drug in such a short space of time. At the same time, the financial implication to accomplish such a task has not been questioned in general. Hopefully one of the approaches described above will prove fruitful and effective. What is more likely is that a combination of approaches will be necessary. For humanity to take a deep breath and move on in to the future with as few casualties as possible an effective vaccine against coronavirus needs be developed as soon as possible. Once effective, humanity will be able to look back at COVID-19 and say that another war has been won and herd immunity has been achieved.
- Wojciech Czardybon, Ph.D.
Drug Discovery Consulting Director, Chemistry