OPINION: In which direction is the research on drugs against COVID-19 progressing?

Manoj Pandey
Stages in which virus can be attacked (pic courtesy: advancedsciencenews)

Stages in which virus can be attacked (pic courtesy: advancedsciencenews)

Disclosure: I am not a medical doctor. However, I do have domain knowledge of human biology, genetics and biochemistry. I have written this article after going through authentic research papers and researchers’ interviews published on the web.

COVID-19 pandemic is likely to peak sometime in April-May, depending upon how it is managed in different countries. The first signs of its control in Wuhan in China are being seen. Strict social distancing is the mantra that seems to be working in containing its fast spread, but there is no standard treatment for it so far. Researchers are working overtime to find a drug or a combination of drugs that work against the infection.

Why is COVID-19 so dangerous?

COVID-19 is a very fast-spreading virus, more than most other known viruses. Among the coronaviruses (the family of viruses causing flu), COVID-19 or the one that originated in Wuhan in late 2019, spreads extremely fast. Within nearly 4 months, 16 million people have tested positive for the virus worldwide, while double that number of people might be harbouring it without symptoms and/or would have recovered on their own. The fast spread itself makes COVID-19 so much dangerous.

Once COVID-19 infects, what makes it extremely dangerous is that it triggers over-activity in the body’s immune system. When that happens, the body releases too many cytokines – chemicals that lead to inflammation or swelling. This hyper-inflammation causes respiratory distress and organ failure. This type of over-secretion of cytokine (called cytokine storm) has also been seen in complications arising due to flu, SARS and MERS. This is why patients often need life-support system including respirators, and why there is so much fatality.

If a person is already suffering from a severe illness of lungs, kidneys and other organs, that makes him/ her highly vulnerable to organ distress. The medicines they might have been taking against existing illnesses can make them vulnerable. That also is a reason why people above 65 years or so are more vulnerable to develop complications than the younger ones.

How actually does COVID-19 attack human cells?

Viruses are pieces of a strand of RNA covered with a sheath of proteins. RNA is a nucleic acid somewhat like the more well-known DNA.

You would know that the genetic material has the potential to recreate (replicate) itself and produce proteins based on what is coded inside it. All living beings live because of the interplay of proteins in cells; all types of chemical coordination and control in multi-cellular organisms including human bodies happens due to thousands of proteins. The enzymes and hormones that lead to numerous biochemical reactions in our bodies are also proteins.

In COVID-19, there are 29 proteins in its shell, which are used for attaching the virus to human cells and compromising the body’s immune system. In a study of 26 out of these 29 proteins, it was found that they can target 332 human proteins to get favourable entry into human cells and then marshal them into submission.

The ‘corona’ or crown that the virus covering has, has spikes, whose tips can bind to human cells through receptor proteins found in human cells. Then a human enzyme unwittingly helps the spike proteins to activate.

Once the viral RNA enters the human cell, it orders the cell to make proteins of its own type, which then spawn more viral RNAs and associated proteins. Thus, numerous new coronaviruses replicate in each cell and infect nearby cells. They are all there in infected person’s saliva and mucus, which act as agents to infect other humans.

When the virus replicates furiously and attacks other cells, about half of humans are able to ward it off but the rest succumb to it. Fine; that happens with other flues also. However, in the case of COVID-19, about 15% of patients’ bodies over-react to the infection. Their auto-immune system gets into overdrive, as if soldiers going mad. Many types of fighter cells come into chaotic action. As mentioned above, one set of chemicals, cytokines, is secreted. These directly or indirectly damage own cells and then spread to other parts of the body, damaging cells there – leading to swelling of the lung lining and other organs and other serious symptoms

The biochemistry/ pathology associated with virus attacks and how the human body reacts to it is much more complex than outlined here. Dozens of chemicals react, dozens of them trigger other reactions.

In the case of viruses, a quick mutation is also a big problem. All genetic material is known to change in minute dozes after many generations, and in the case of viruses, a lakh generations happen within no time. Luckily, COVID-19 is found to mutate much less as compared to other flu viruses.

What are the types of treatments being looked at?

As would appear from above, if we have to treat COVID-19 infection, the key could be
– to check the viral proteins from attaching to human cells and getting activated;
– to check proteins that compromise internal anti-viral system from working;
– to stop the replication of the virus inside cells.

In addition, we must look at ways to reduce the severity of symptoms., because some of the reactions of the body are more dangerous than the infection itself.

A completely different set of studies are being done on which chemicals or devices can neutralize the virus in air or on surfaces where virus-laden droplets fall. Also being studied are whether it can be transmitted through stool or blood, whether transfer from humans to other animals can occur, methods of quick testing and so on. I have excluded these from the present discussion to focus on finding a drug for treating COVID-19 patients.

It is clear that a combination of drugs has to be used, to manage infection as well as serious symptoms. Since the spread is fast and fatality is high, there is no time to depend on academic research and procedures that take years to develop one single drug molecule. A faster way out seems to be to examine drugs that are in use against other diseases or are in advance stages of trials. It is reported that about a hundred drugs in use or in advance trials have been identified and are being tested for COVID-19 treatment.

Scientists are also looking deeper into the working of viral RNA and proteins, which will help in attacking the virus in its vulnerable spots and not allowing it to exploit vulnerabilities in the human system.

As expected, one branch of research is focusing on stopping the viral protein from attaching and getting activated. That is leading to a vaccine that was useful against SARS and MERS – whose viruses also have corona and spikes; the vaccine is in fact in a very advanced stage of testing. Hydroxychloroquine, an anti-malaria drug, is also supposed to inhibit this process.

Anti-viral drug remdesivir – the one being tested and even used for COVID-19 – stops one step in the replication process of viral RNA within human cells. Researchers are checking whether other known anti-viral drugs can be useful.

One branch of study is looking at tempering the auto-immune system so that it does not over-react. Drugs that are in use for calming down the auto-immune system during cancers, rheumatic arthritis etc are potential candidates. These inhibit anakinra, tocilizumab and ruxolitinib. They inhibit production or activity of some proteins in the chemical chain that causes hyperactivity. Similarly, hydroxychloroquine has also been found to be effective in tempering and over-excited immune system. Some of these have already been authorized for use in case of COVID-19 and have shown good results.

It has also been found that blood transfusion from recovered patients is effective in treating others. This is because this blood has developed antibodies that can stop the corona spikes from being received by human cells, much like vaccines. By the way, it is also being examined whether any commonly used vaccine (e.g. BCG vaccine) has something to offer against COVID-19.

As of now, many of these drugs have been approved for clinical trials and some are actually being administered to patients. Some of them have toxicity and side effects, and therefore cannot be given to all patients. In some cases, a drug effective on some patients has been seen to be ineffective on others, partly because the stage of infection and overall medical condition of each patient plays a major role in determining how he/ she responds to infection and medical treatment.

Why is hydroxychloroquine (HCQ) so much in demand? Is it proven to be effective against COVID-19?

As explained above, HCQ seems to make it difficult for the virus to enter human cells and also calm down the auto-immune system. Many countries have permitted its trials and use on COVID-19 patients. However, clinical trials have not yet proved its efficacy specifically in the case of COVID-19.

Since doctors are clutching at straws in absence of any proven medicine against COVID-19, HCQ is in high demand. US President has been advocating its use, and once even threatened India with reprisals in case it did not allow export of HCQ to the US. India is a big producer and consumer of HCQ and, after ensuring that it has enough stocks to meet the domestic requirement, has allowed its export to other countries.

How soon can you expect a proven treatment against COVID-19?

It is good to know that in such dire situation when nearly 96,000 people would have died of this virus globally before this weekend, international organizations, countries, research labs, institutions and manufacturers have joined together to come out with medicines against the virus. Research coalitions and a genome sequencing alliance have been formed for collaboration and exchange of research data. Funds have been flowing from public and private organizations, governments and international bodies. Trial periods of many drugs have been shortened, many countries have permitted clinical trials, and even trials on volunteers have started.

However, it is also apprehended that many labs and manufacturers will keep close to their heart the molecules they discover as potent. Some may not be cooperating with international effort, only paying lip service. Even when a drug is found effective, its supply on a large scale at a short notice may not be easy. Authorities are also known to be slow in granting permissions, especially for trials, for fear of negative consequences and ethical concerns.

The shortest timelines towards finding a focused cure against COVID-19 look like this:

• More effective, experience-based, use of medicines already being administered: on-going; may reach near-satisfactory level by early May.
• Wide-spread use of blood plasma from recovered patients if proves effective: mid-May.
• Identification of existing drug(s) as effective against COVID-19: May-June. Mass production: June onwards.
• Vaccine: no sooner than 6-8 months, to be optimistic.

-Manoj Pandey