Drugs and Effects
With one of the world’s greatest outbreak of coronavirus and its symptoms and effects that the planet is coping with, there are already a lot of rumors and answers and thousands if not millions of blogs, memes, videos, and websites on the do’s and don’ts for the disease. But what I am writing about today is not from a perspective of the do’s and don’ts and how this virus effects humans, but from a scientific point of view of the drugs and their mode of action.
This article is not specific to coronavirus, but irrespective of the context of any infectious disease, and how it is similar yet distinct from other deadly diseases like cancer. The first question that should come to your mind is who I am and why should you believe me. You are not bound to believe what I say or state. In fact, I would encourage discussions and arguments about the facts that I state, given there is better evidence available. I am a Biochemistry and Structural Biology PhD student currently in my second year in Stony Brook University, out in Long Island, New York. Long Island is facing quite many cases of COVID-19 till date, March 23rd. My research focusses on developing drugs against multi drug resistant strains of Mycobacterium tuberculosis, TB, as is commonly called. Before joining the current team for my dissertation research, I worked on several research topics and in various labs on the drug design aspects of diseases like cancer, fungal pathogenic diseases and immunodeficiency diseases.
Throughout history, researchers have tried hard to devise measures and drugs for deadly diseases like anthrax, smallpox, malaria, cholera, and all other epidemics. On the other side, diseases like cancer, obesity, diabetes, and heart diseases remain a threat and pose challenges, but from a point of view different from infectious diseases. Firstly, chronic underlying diseases like the aforementioned ones are not contagious, whereas most infectious diseases are. Also, they are not mediated by external pathogens, but through dysregulation of normal cells. Therefore, the treatment and diagnosis for infectious vs chronic underlying diseases have a different paradigm but intertwines and overlaps somehow in the individuals coping up against the disease. The most important term that makes the difference is immunity. The stronger the immune system, the better. People suffering from cancer are more likely to have a compromised immune system because of the treatment that they undergo and hence they are more vulnerable to pathogenic infections because of suppressed or inadequate immune response. That is why a lot of cancer patients show symptoms of pneumonia few days before they die.
Usually, drugs are organic molecules that are synthesized in laboratories and tested to block the physiological action of certain proteins usually enzymes that evoke pathogenicity. In other words, these organic molecules look similar to the physiological binding partners of the pathogenic molecules and serve as analogues and block their function. But this is easier said than done for most diseases that are deadly like cancer, obesity, HIV/AIDS etc. Most drugs fail in the second or third stage of clinical trials. In case of infectious diseases, all drugs for bacterial, fungal, and viral infections function by blocking either the entry of pathogen inside the human cells or by disrupting the machinery of their survival inside the human cells. In this context, antibiotics have an easier mode of action on the superficial realm as they act on bacteria, which fall among prokaryotes (the cells are more primitive than humans and have different mode of action). However, for fungal infections, drug discovery and design gets harder as fungi are eukaryotes having a similar cellular architecture to humans. In this case, drugs in action might disrupt the normal function of the cells. Selectivity to the pathogen versus the host is the key that defines success.
Even more complicated are viral pathogens because of their mode of infection. Viruses usually take the host cells machinery to perform its tasks. Hence disrupting the viral machinery alone, remains a challenge, as that might affect the host cells machinery too. Though the approach to disrupt the viral replication is a possible mode of drug action, the more potent way is to stop its binding to the cell and prevent its entry. With a lot of viruses like mumps, measles, smallpox, polio, hepatitis, and influenza (flu), vaccine development had been easier. In the course of natural infection, after an individual is affected by these viruses, they develop immunity to the viral strain which remains as a memory in the immune system. Hence, when vaccines were developed, they mimicked natural infection by using live attenuated viruses, thereby providing immunity in the healthy individual if the immune system ever encounters the virus. But in certain viral infection, like HIV/AIDS, the method of vaccination using live attenuated viruses does not work.
In the context of COVID-19, it is not yet known whether the vaccination would be more helpful through organic molecule, a drug that blocks the function of the virus, or a live attenuated virus that provides immunity, or antibodies capable of binding viruses and neutralizing them. It is important to keep in mind that coronaviruses have a high mutation rate and it changes its host over time, from bats to pangolins to humans. It has been stated in scientific literature already that bats are hosts for a substantial number of coronaviruses, but since these studies are limited in bats, the definite number cannot been reported. However, by doing genetic analysis, it has been found that, with SARS CoV-2, the genome sequence is different from that of the viral homologue in the bats, and since it mutates and infects rapidly to meet the demands of the host, it is possible that the virus would soon evolve and step up to a new host, declining human hosts.
Today people have the electron micrograph pictures of the coronavirus. Recently a lab in the University of Washington has published the structure of the spike protein that is present in the outermost shell of the virus required for binding to the human cell. This information gives us an overview of how the virus looks like and what might be a good drug target.
COVID-19 being an infectious disease has similar symptoms with others like malaria, flu etc. The mode of infection of this virus also overlaps with the member of its family like influenza, and hence drugs that have already been tested might come in handy. For example, it has been reported in the news that the combination drug hydroxychloroquinone with antibiotic azithromycin, or chloroquinone alone showed remarkable effects in diminishing symptoms of COVID-19 in the infected patients. It is not a full proof evidence as it is a potent drug for malaria and there has not been enough data from the clinical trials that will support with confidence that the drug for malaria would cure COVID-19. In this regard, I would actually mention what Dr Fauci, the eminent scientist in Infectious Diseases in NIH and also the leader in the coronavirus control team under the Trump administration said, “It might be the case the drug might show results, but it is not certain. As a scientist, I first want to prove what it does and show the evidence. The drug might or might not work. The drug was effective in the context of malaria which might not be the case with COVID 19”. The take home message is, drugs have to be effective in context of a specific disease. In the context of COVID-19, it is not certain whether it would show specific effect, unless clinical trials and data show the evidence. But looking at overlapping functions and mode of actions of these pathogens, it is more likely that some drugs would have overlapping effects in reducing the symptoms of the disease.
Another aspect that needs attention is following directions while using our brains. I want to focus on the word “brains” because over the past few weeks, I have witnessed my friends, relatives fleeing states and dorms in the fear of the disease, wearing masks and gloves as either the institution made it mandatory or for self-protection, but the effort has not been hygienic. If you wear masks, and gloves, learn about contamination and how it works. Being a biochemist, spending all my days in labs, and working with cell lines, or pathogenic microbes, my brain is trained to witness this virus, from the hygiene point of view. But for people who have never worked in labs or have no idea of how to sanitize and prevent contamination of body parts, now is the time to train your minds. I have seen fellow students wearing gloves and reusing them or reusing masks that fell from their hand. Although it might not come to your attention, you might infect yourself even after wearing contaminated protective equipments. The problem is it is impossible to visually see a microbe, and therefore imagining a microbe and keeping in mind what it can do to you, is hard. But only practice can help, and this might actually be an opportunity to imagine and dream about things we can’t see or perceive with senses.
A commonly stated phrase that one of my professors of immunology repeated in his lectures is “War is the mother of all inventions”. Every epidemic throughout history are essentially wars, because it comes with a socioeconomic toll. I have never survived wars, and this has been my first experience of surviving a global crisis. It’s not a personal problem, as the planet is running on the same boat, as you are. Things would get better, so be patient and things will fall in place. It has already been predicted that in the next few months, 3 million Americans would be unemployed. You can fight with humans, but can you fight with something that you cannot see or sense? Can you forward your message about how important your job is and how useful you are to this world? No. It’s beyond human capacity. Globally, a virus, just a few microns in dimension, is determining lives of humans. In the 21st century, when we are traveling through space and visiting other planets, it almost seems amazing and astonishing, how a microbe seemingly so small and powerless, has turned the planet upside down. How insignificant and impermanent is our lives! However, as the saying goes, “Every ending is a new beginning”. This might be the end for some, but I believe it will be a beginning for the majority.