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.