Breaking Down the Biology Behind COVID-19 Therapeutics
Lately, there has been a lot of buzz about COVID-19 therapies as the US starts to ramp up clinical trials for promising drug candidates. In today’s post, we’ll touch on the biology behind how these potential therapeutics may treat COVID-19.
What are the potential therapeutics for COVID-19?
Generally, potential therapies for COVID-19 are broken into 2 categories:
Antiviral therapies — These drugs target the virus by inhibiting a specific step of the viral life cycle. This includes the ability of the virus to infect (enter) our cells, make more of itself (replicate and assemble), and exit the cell (release). Many antiviral drugs have been approved to fight numerous viral infections over the past 50 years. Among these are anti-retroviral therapies for HIV as well as the flu antiviral therapy, Tamiflu (oseltamivir).
Possible targets for antivirals in the coronavirus life cycle. Image source: https://science.sciencemag.org/content/early/2020/05/07/science.abb9332/tab-figures-data
2. Host modifiers/Immunotherapies — These are drugs or biologics that modify our cellular or immune response. The general idea behind immunotherapies underlies the fact that immune responses function in a balanced and controlled state in healthy people, but this balance can be disrupted in disease. This is best illustrated in autoimmune disease (too much immune response) and cancer (too little immune response), but can also occur during infection. Some immunotherapies dampen the immune response when it goes into overdrive and becomes detrimental to our well-being - you might have heard the term “cytokine storm” from people talking about the 1918 and 2009 influenza pandemics. Immunotherapies are often developed for the treatment of autoimmune diseases like lupus and rheumatoid arthritis. There are also immunotherapies that boost the immune response to help us fight certain cancers. While immunosuppressive therapies commonly used for autoimmune disease are not often prescribed for viral infections, they may be helpful in the fight against COVID-19.
Illustration of the delicate balance of immune system function. Image source: Drug Discovery World
Antivirals currently in trials for treating COVID-19
Remdesivir: This drug was initially developed for the treatment of Ebola, but was not effective in that context. In vitro and animal models suggest it may be effective against coronaviruses, including SARS-CoV-2. A massive NIH-sponsored multi-center trial is underway for Remdesivir and promising early results are already being reported. Its mechanism of action is to specifically inhibit viral replication.
HIV anti-viral therapies (lopinavir/ritonavir): These therapies were developed to reduce the viral load of HIV in HIV+ individuals. Their mechanism of action is to target a viral enzyme (specifically a protease) to prevent viral function. Cell culture data for the activity of this drug against SARS-CoV (the original SARS virus which emerged in 2003) was promising. However, these drugs have yielded negative results in people in China (additional studies detailed at this link). This is likely because SARS-CoV-2 is not as sensitive to the drug as HIV and therefore the dose needed for COVID-19 treatment would be intolerable.
Host modifiers/immunotherapies currently in trials for treating COVID-19
Convalescent plasma transfer: This therapy uses plasma isolated from people who have recovered from a SARS-CoV-2 infection and who developed a strong antibody response. The plasma (which contains antibodies) is transferred into a sick individual, where the antibodies can immediately target the virus before the infected individual can ramp up their own protective antibody response (which takes weeks and is also the goal of vaccination). This type of therapy has been effective for the treatment of other infections. Patients in the US have started to receive convalescent plasma transfer therapy for COVID-19. Side note: A further discussion about antibodies is linked here.
Cytokine inhibitors: These therapies have been developed for autoimmune and autoinflammatory conditions where the immune response becomes detrimental to our well-being. They target soluble factors (cytokines) that ramp up the immune response. There is evidence that some people infected with SARS-CoV-2 may become severely ill due to an overactive immune response to the virus. These drugs have been discussed as a potential way to limit those effects but have not yet been studied in this context.
How convalescent plasma transfer works. Image source: Johns Hopkins University
Current therapy in trials that may act as an antiviral and immune modulator
Chloroquine/hydroxychloroquine: Chloroquine was initially developed in the 1930s as an anti-malarial. It and its derivatives were later adapted for use in autoimmunity (lupus and rheumatoid arthritis) due to their immunosuppressive properties. The potential mechanisms of these drugs are wide. They may prevent viral entry into the cell, suppress the immune response, and may block viral release. Cell culture studies have shown the ability of hydroxychloroquine to be effective against SARS-CoV-2 in vitro (this means the experiment was done in a dish and not an animal model). While this treatment has been studied and mentioned the most so far, it is hard to fully interpret its effectiveness due to the various ways the studies were conducted and the mixed results received (all summarized here). Cardiac side effects have also been reported, which must be considered. In short, current studies suggest chloroquine is not an effective anti-viral for SARS-CoV-2.
To summarize, there are numerous therapeutics being assessed for COVID-19, each of which have a distinct mechanism of action. The timing of administration (early versus late) and use in specific subsets of patients may be very important and contextually dictate which therapies may be most effective. We hope you enjoyed our short Part 2 of ‘Breaking down the biology.” As always, the science and research on COVID-19 is rapidly developing, so this post reflects data current of May 10, 2015.
Stephanie Schell, PhD
Stephanie received her PhD in Virology and Immunology from the Penn State College of Medicine in 2019. For her PhD, she studied B cell and antibody responses induced after immunization and in the autoimmune disease, lupus. She is currently a postdoctoral scholar at the Penn State College of Medicine, working on several translational projects that focus on inflammatory skin diseases. When she isn’t in the lab, Stephanie enjoys being outside and competing in sports.