Introduction
The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic by the World Health Organisation (WHO) on March 11, 2020 (https://covid19.who.int/). A rapid rise in the numbers of COVID-19 cases followed (Paules, Marston, & Fauci, 2020) and as of September 2021, there have been over 226 million cases of COVID-19, including 4.6 million deaths. Health care systems have been globally overwhelmed (Miller, Becker, Grenfell, & Metcalf, 2020) and projection studies predict that rapid transmission dynamics will potentially be at play well into 2025 (Kissler, Tedijanto, Goldstein, Grad, & Lipsitch, 2020). Although viral vector and mRNA vaccines have been developed, they can result in serious adverse effects such as life-threatening thromboembolic events and anaphylactic reactions. Additionally, geopolitical logistics and vaccine nationalism make it unlikely that these vaccines will be equitably available across the globe for a few more years. Furthermore, global herd immunity is unlikely to be achieved due to the evolution of new variants of concern. Therefore, vaccines alone cannot be sufficient in controlling the pandemic nor in treating its complications in more susceptible individuals. Effective novel therapeutic interventions must be developed rapidly. Despite intensive and collaborative research efforts, treatment options remain limited. Remdesivir (Beigel et al., 2020), dexamethasone (Horby et al., 2021) and IL-6 antibodies are the primary treatment options currently approved (Rochwerg et al., 2020) for COVID-19 but they can result in serious systemic adverse effects and only moderately affect clinical outcomes. The limitations of these therapies highlight the need for ongoing development of life-saving medications to help fight the virus.
Coronaviruses (CoVs) are large, enveloped, positive sense and single-stranded RNA viruses belonging to the family Coronaviridaewithin the order Nidovirales (Y. Chen, Liu, & Guo, 2020). They can infect several mammalian hosts and are divided into four genera: alpha, beta, gamma, and delta, of which alpha and beta CoVs are known to infect humans. Full-genome sequencing and phylogenetic analyses have indicated that the CoV that causes COVID-19 was in the same subgenus as the SARS virus (Fehr & Perlman, 2015) and was named on the basis of its appearance under electron microscopy. Human CoV infections usually cause mild, self-limiting respiratory infection. However, the epidemics of SARS-CoV and Middle East respiratory syndrome coronaviruses (MERS-CoV) caused alarming morbidity and mortality in 2002-2003 and 2012 respectively (Gao, Yao, Yang, & Li, 2016) and COVID-19 has underscored the continued risk of pandemics caused by such viruses. Risk factors for severe COVID-19 across the globe include older age, race, gender, obesity, cardiovascular disease, diabetes, chronic lung disease and immunosuppression. Therefore, drugs which target pleiotropic mechanisms may be important. Coronaviruses have a large genome and a higher mutation rate compared to other RNA viruses, hence eradicating them definitively is difficult (Gralinski & Baric, 2015). Broad-spectrum inhibitors of emerging CoVs are therefore needed and repurposing existing drugs has been validated as a means to tackle the SARS-CoV-2 pandemic as well as enabling future pandemic preparedness.