As we gradually transition into the fourth phase of the nationwide lockdown, we continue to implement strong defensive strategies against the novel coronavirus, including fast and reliable diagnostic procedures, as well as plans that limit the spread of the contagion. However, to be effective, these must be combined with equivalent offensive tactics against the virus, such as drugs and vaccines.
This concerted “defence & attack” approach is necessary for eradicating this deadly pathogen. An effective and successful “offensive” approach will ultimately depend on formulating and developing both prophylactic (preventive) as well as therapeutic (treatment) strategies to fight SARS-CoV‑2. Such strategies can only be developed if we combine our scientific knowledge from previous viral infections with modern scientific and technological advancements.
In the first part of this article, we discussed how understanding the novel coronavirus’s biology helps us devise methods to restrict its spread and quickly diagnose its presence in patient samples. This second part will focus on the wealth of knowledge we have gained from previous such viral infections of pandemic proportion, and how some of these have been translated to SARS-CoV‑2 research with an aim to discover novel therapeutics.
Developing therapeutic strategies
The need of the hour is to develop drugs against this deadly virus – which is easier said than done. Before we come up with strategies to fight the virus, we need to study its behaviour closely to understand which of its essential processes we can target.
Currently, researchers are following three main approaches. The first approach is to find a drug that can prevent the virus from entering the cell. However, for this, we need to understand exactly how the virus enters the host cell. The second approach is understanding how the virus replicates inside the host cell and developing agents that could block this replication cycle. Finally, in the third approach, researchers are also investigating if drugs which are already approved and available commercially can be repurposed to target COVID-19.
Strategy 1: Targeting SARS-CoV‑2 binding to the host cell
A little over a month after the first reported COVID-19 case, a group of researchers led by Jason McLellan from the University of Texas published a detailed structure of the viral “S” protein (which forms its spiky outer layer) and highlighted how it is used by the virus to bind to the host cell. This study demonstrated that the virus uses a “Lock and Key” mechanism to attach itself to the host cell, which is the first step in the infection process.
In this, the viral “S” protein acts as the “Key” which attaches itself to a human protein, ACE2 (Angiotensin Converting Enzyme), which acts as a “Lock”. ACE2 is present on several human cells including the cells that line our lungs. This attachment is essential for viral entry into the host cell, and therefore presents a unique opportunity to scientists, as any molecule that can disrupt this attachment can be potential drug candidates.
Another study, published at the beginning of March 2020, provides more support to this approach. In this study, a group of researchers from the Leibniz Institute for Primate Research, Germany, working under the leadership of Stefan Polhmann demonstrated that another protein, TMPRSS2 assists in viral entry into the host cell by priming the spike protein “S”. This study also highlights how a synthetic inhibitor, Camostat Mesylate, can target this viral protein and blocks the virus from entering the host cells. This kind of breakthrough research opens up possibilities of new drug discovery which targets the virus-host attachment.
Strategy 2: Targeting SARS-CoV‑2 replication inside the host cell
Researchers have also been trying to find ways to target viral replication — the process through which the virus multiplies once it’s inside the host cell. A ground-breaking study by a group led by Rolf Hilgenfeld at the University of Lubeck, Germany, described the detailed structure of another viral protein, Mpro, which plays an integral role in viral replication. The researchers also showed that the reproduction of the virus inside the cells could be blocked by using an inhibitor, α‑ketoamide, thereby offering a promising strategy for potential therapeutic intervention.
Strategy 3: Repurposing already approved drugs
Alternate strategies for treating COVID-19 may stem out of repurposing drugs that are already in the market for other diseases and disorders. Already antiretrovirals, which have been used to treat HIV infections, are being explored for their efficacy against COVID-19. However, these have had limited success, and the findings from the trials have been somewhat contradictory. Very recently, a laboratory study highlighting a combination of Remdesivir, an antiviral drug, and chloroquine, a common anti-malarial drug, has shown great promise against SARS-CoV‑2.
Just recently, Remdesivir alone has shown tremendous promise in a group of patients with COVID-19 and is presently under clinical trial, conducted by GILEAD, USA. These results were backed up by another publication showing that hydroxychloroquine, a derivative of chloroquine, can inhibit lab-grown SARS-CoV‑2 with minimal toxicity. Another drug combination — Azithromycin and Hydroxychloroquine — has also been shown to show positive results on COVID-19 infected patients in a study by researchers at IHU-Méditerranée Infection, Marseille, France, although these studies need further evaluation with larger groups of patients. An FDA-approved anti-parasitic drug, Ivermectin has also been shown to have potent antiviral activity against SARS-CoV2. In another comprehensive study, a large scale screening of already available drugs identified 30 potential drugs that could block viral replication.
As I am writing this update, over 4.9 million confirmed cases of COVID-19 have been reported worldwide with more than 3 lakh confirmed deaths. But researchers always try to find the little rays of hope within the grey, and the positive news here is that over 1.9 million people have recovered worldwide. This means that all these people who have recovered are now harbouring priceless antibodies against this deadly virus in their bloodstream. Utilizing this anti-sera from people who have recovered from COVID-19 may provide an excellent strategy to fight this infection.
In fact, during the SARS and the MERS pandemics a few years back, sera with antibodies from recovered patients were used to successfully treat patients with an active infection. The possibility of using such an approach for COVID-19 has also been under discussion. Recently, a purified but inactivated SARS-nCoV‑2 virus has been shown to be promising as a vaccine candidate.
An emerging idea in the treatment of COVID-19 is to study human subjects who are naturally resistant to the virus. If we are able to identify subsets of people who are naturally resistant, comparative gene sequencing of such naturally resistant people with COVID-19 susceptible patients may unravel a treasure trove of data, which may assist in effective drug development against this virus. In fact, not long ago, studying people naturally resistant to the deadly virus HIV gave us invaluable clues about their immunological profile, which played a significant role in the development of anti-HIV treatment strategies.
Indian Initiatives on COVID-19 research.
On the Indian side as well, initiatives on COVID-19 research have been taken up quickly. While a core team of professionals has been formed to formulate strategies to combat COVID-19, the country’s scientific organizations like DST have set up their own COVID-19 task force to accelerate diagnostics and R&D to boost the country’s effort to mitigate COVID-19. Basic research to understand the genomics of the virus infecting Indian population, as a first step towards effective drug development, has been reported in several pre-print publications. DNA sequence analysis of the S‑protein from Indian isolates has revealed a critical amino acid change in the viral S‑protein which might affect its infectivity in the Indian population. Similarly, Indian researchers have been working on the identification of potential drug targets and vaccine candidates against SARS-CoV‑2.
Past, present, and future
Hope is not lost. In fact, what history has shown us is that the human race persists. Also, all this while, we have been thinking of the virus as a constant entity without any change, but this is not true. As the virus infects more and more people, it encounters new micro-environments inside the human body and accumulates small changes. Evidence from both the SARS and Ebola epidemics has shown that with increasing infections and onward transmissions, the number of mutations in the virus’s genome also increases.
Many of these mutations do not affect the virus’s pathogenicity. Often they reduce the harmfulness of the virus, by reducing its infectivity or capacity to cause death. This is because a virus cannot live by itself — it needs a viable host. Hence the virus always looks for environments where it can thrive, even if it comes at the cost of its ability to cause disease. In fact, the Global Initiative on Viral Data Sharing has shown that SARS-CoV‑2 genome has undergone mutations several times. Even the SARS-CoV‑2 strain isolated from Kerala, India has undergone several mutations compared to the original Wuhan strain. Whether these mutations alter the virus’s pathogenicity in the long term is yet to be studied.
Finally, I would like to end on a slightly more philosophical note. Why are these outbreaks occurring at this particular period during human history? Do the increasing technological advancement of the human race and changing ecology have anything to do with this? Epidemiological data and genetic sequence analysis show that many of these coronavirus strains might date as far back as ~ 5000BCE or even earlier. Many of these originated in animal hosts, particularly bats. These viruses have undergone mutations and exchanged hosts several times before transferring to humans. Are the changing climate, increasing pollution, and modernization in any way responsible for inducing critical mutations in these viruses, that enable them to be transferred to humans? Why are bats resistant to such viruses?
These questions prompt different perspectives, and hence alternate approaches to solve these mysteries. The answers to these questions might be critical in dealing more effectively with this kind of crisis. If anything, this global pandemic has paved the way to the inevitable realization that the development of a supportive environment towards promoting scientific culture and temperament is essential towards tackling such pandemics in the future.
And towards meeting these ends, policymakers globally have to prioritize the promotion of a better scientific environment and practice, both intellectually as well as financially. The most powerful message that has come out of all this is that the human race is capable of presenting a united front against a crisis, in spite of whatever geographical, racial, and religious borders may exist. With a species so determined to persist, a minuscule virus won’t be able to defeat us so easily.
This is a companion discussion topic for the original entry at https://indiabioscience.org/columns/opinion/the-role-of-science-and-scientists-in-mitigating-the-covid-19-pandemic-part-2