By Souheil-Eddine Zitouni
Over the past couple of months, two oral antiviral drugs have been branded to reduce COVID-19 deaths and admission into hospital after clinical studies of patients treated readily after initial infection. If these trends are replicated in a real-life setting, these antivirals could forge the next chapters of what has seemed to be an ever-lasting pandemic. This therapeutic avenue is not new and was considered earlier in the pandemic, however, previous antivirals effective against SARS-CoV-2 were disproportionately expensive to manufacture and required a hospital setting for administration.1
These new drugs, with one being manufactured by pharma giant Pfizer (Paxlovid) and the other by Merck (Molnupiravir), are small molecules that can simply be used at home and are much cheaper to produce than previous alternatives considered earlier in the pandemic. This is especially important for developing countries with poor vaccine coverage which would be able to access a viable therapeutic to alleviate COVID-related hospital admissions. However, with these antivirals being so new, not much is known concerning how effective they will turn out to be and what potential side effects they might have. Therefore, this review explores key factors that will undoubtedly dictate the next turn of events in this pandemic.
Efficacy of the new antivirals
As the full reports from the clinical trials have yet to be released, it is still hard to determine if both drugs can reduce hospitalisations and deaths from COVID-19 if administered soon after infection in a real-life setting. However, according to numerous press releases, this was observed to be the case albeit with some key details yet to be disclosed. For example, factors such as the age and ethnicity of those who participated in the clinical trials remain to be evaluated as well as when these drugs were administered after infection. These are important variables to take into consideration as there may well be a correlation between them and the efficacy of these drugs which leads to the determination of the window of opportunity for usage. Nevertheless, if these drugs can affect the transmission of SARS-CoV-2 or prevent illness in subjected individuals, their usage in a combinatorial manner with vaccines paves the way for a robust tool to control for potential outbreaks. This is especially relevant when considering emerging variants that have been an area of concern concerning coverage that current vaccines offer.
How do the antivirals work and are they safe?
Molnupiravir works by incorporating mutations within the viral genome during viral replication. Once processed, a metabolite of this small molecule binds to viral RNA-dependent RNA polymerase (RDRP) being incorporated in the viral genome, leading to a vast number of mutations that inhibit virus survival.2 A potential risk with this approach is that although human genomes consist of DNA, Molnupiravir could influence DNA polymerases to introduce mutations during DNA replication in a similar manner to its mechanism with RDRP. This is especially concerning for pregnant women, meaning that this antiviral will most likely be accompanied by a host of warnings due to the potential implications. On the other hand, Paxlovid is a mix of the antiviral PF-07321332 combined with a low concentration of Ritonavir which is an antiretroviral typically used against HIV. This combinatorial treatment disturbs viral replication via the binding to 3CL-like protease which is of paramount importance for viral reproduction and functionality.3 Another major concern is that Ritonavir can affect other intracellular drug metabolism pathways and hence will not be available for certain patients undergoing other treatments which greatly reduces its usage.
Sars-CoV-2 antiviral resistance?
Drug resistance is an ever-growing issue that plagues small molecule therapeutics as the essence of druggable targets leads to selective pressures to pick for the fittest organisms. This is a familiar issue concerning some viral infections including hepatitis C and HIV4 which require a cocktail of antivirals for effective treatment. This is also likely to be the case for Paxlovid and Molnupiravir which have only been trialled as single therapies. Hence, it is of crucial importance to examine patients that exhibit no therapeutic benefits when administered with these drugs to evaluate if viral resistance could potentially be a factor, especially in immunocompromised patients as infections typically last longer which enables opportunities for resistance to arise.
As suggested throughout, only further studies could determine if these antivirals will be able to write the following chapters of the COVID-19 pandemic story. Nevertheless, large orders from high-income countries seem to suggest its viability as a combinatorial treatment with current vaccines as well as seemingly repeating previous mistakes by soaking up drug supplies and limiting access to developing countries which appears to be an all too familiar story.
References:
1. Ledford H. Antibody therapies could be a bridge to a coronavirus vaccine — but will the world benefit? Nature (London). 2020; 584 (7821): 333-334. 10.1038/d41586-020-02360-y.
2. Venkataraman S, Prasad, Burra V. L. S., Selvarajan R. RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution. Viruses; Viruses. 2018; 10 (2): 76. 10.3390/v10020076.
3. Muramatsu T, Takemoto C, Kim Y, Wang H, Nishii W, Terada T, et al. SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proceedings of the National Academy of Sciences – PNAS; Proc Natl Acad Sci U S A. 2016; 113 (46): 12997-13002. 10.1073/pnas.1601327113.
4. Strasfeld L, Chou S. Antiviral drug resistance: mechanisms and clinical implications. Infectious disease clinics of North America; Infect Dis Clin North Am. 2010; 24 (3): 809.
5. Willyard C. How antiviral pill molnupiravir shot ahead in the COVID drug hunt. Nature (London). 2021; 10.1038/d41586-021-02783-1.
6. Dolgin E. The race for antiviral drugs to beat COVID – and the next pandemic. Nature (London); Nature. 2021; 592 (7854): 340-343. 10.1038/d41586-021-00958-4.
Imperial Bioscience Review 