A pipeline of effective direct-acting antivirals (DAAs) remains a critical gap in addressing the current pandemic given vaccination hesitancy, the emergence of viral variants of concern, susceptible populations for which vaccination is ineffective or unavailable, and the possibility that coronavirus disease 2019 (COVID-19) is here to stay. Since the start of the pandemic, global efforts in small molecule drug discovery have focused largely on testing of FDA-approved drugs to accelerate evaluation in clinical trials in hospitalized patients. With 80% of the population who test positive for SARS-CoV-2 having asymptomatic to mild COVID-19, early stage, DAAs would be of enormous benefit to reduce spread, duration of symptoms and quarantine length. We highlight a few of the most promising DAAs in clinical trials and discuss considerations in how to navigate the challenges and pitfalls of novel small molecule discovery and thereby accelerate the advancement of new, safe, and oral DAAs.
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