Abstract
In vitro drug screening has been a widely used approach to identify therapeutics for the treatment of many infectious diseases, including COVID-19. In late December 2019, a novel coronavirus (SARS-CoV-2, the etiological agent of COVID-19) emerged in Wuhan, China. This new virus rapidly disseminated across the globe, leading to the ongoing global pandemic. Vaccination is an integral part of a global strategy to control this and any other viral pandemic, the other being effective antiviral drugs. However, the lack of antivirals has posed a huge challenge to containing and controlling the SARS-CoV-2 outbreak. For the first two years of the COVID-19 pandemic, the only FDA approved treatments for COVID-19 (i.e., the nucleoside analogue remdesivir and a few monoclonal antibodies) required intravenous administration. It was only in late December 2021 when two orally bioavailable drugs, nirmatrelvir/ritonavir (Paxlovid®) and molnupiravir (Lageviro®) received approval by regulatory agencies to be used in COVID-19 patients. Therefore, adding new anti-SARS-CoV-2 drugs to our armamentarium to combat this highly transmissible virus has been the goal, and challenge, from day one. This must include a multi-target treatment approach to limit the possibility for the selection of resistant viruses, which can be achieved through developing a range of drugs against different molecular targets in the viral life cycle. The main goal of this study was the identification of small molecules capable of inhibiting SARS-CoV-2 in vitro. For that, we started by implementing a reproducible cell-based drug discovery system to quantify both cellular toxicity and antiviral activity, using relevant cell lines and SARS-CoV-2 strains isolated in New Zealand. Following the screening of 263 local compounds, we identified four hits: three unknown natural products (VUWCOV059, VWCOV267, and VUWCOV270) and one previously identified (VUWCOV194 or galidesivir). Compounds VUWCOV059 and VUWCOV267, as well as galidesivir seem to inhibit SARS-CoV-2 entry. Ongoing studies, including the in vitro selection of viruses with reduced susceptibility to the novel and known antiviral agents, will help us discern the mechanism(s) of action of these compounds. It is clear, based on our history with multiple viral infections, including other coronaviruses, that a panel of deployable effective antiviral therapeutics is extremely invaluable for controlling any viral pandemic, including establishing a first line of defense for new or remerging sarbecoviruses.