Use of Tox21 Screening Data to Evaluate the COVID-19 Drug Candidates for Their Potential Toxic Effects and Related Pathways

Currently, various potential therapeutic agents for coronavirus disease-2019 (COVID-19), a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are being investigated worldwide mainly through the drug repurposing approach. Several anti-viral, anti-bacterial, anti-malarial, and anti-inflammatory drugs were employed in randomized trials and observational studies for developing new therapeutics for COVID-19. Although an increasing number of repurposed drugs have shown anti-SARS-CoV-2 activities in vitro, so far only remdesivir has been approved by the US FDA to treat COVID-19, and several other drugs approved for Emergency Use Authorization, including sotrovimab, tocilizumab, baricitinib, paxlovid, molnupiravir, and other potential strategies to develop safe and effective therapeutics for SARS-CoV-2 infection are still underway. Many drugs employed as anti-viral may exert unwanted side effects (i.e., toxicity) via unknown mechanisms. To quickly assess these drugs for their potential toxicological effects and mechanisms, we used the Tox21 in vitro assay datasets generated from screening ∼10,000 compounds consisting of approved drugs and environmental chemicals against multiple cellular targets and pathways. Here we summarize the toxicological profiles of small molecule drugs that are currently under clinical trials for the treatment of COVID-19 based on their in vitro activities against various targets and cellular signaling pathways.