Repurposing approved drugs as potent antiviral combinations to treat COVID-19 disease

We hypothesise that antiviral drug combinations against SARS-CoV-2, suitable for oral or intranasal administration, will provide therapeutic opportunities for ambulatory COVID-19 patients that are more efficacious and with less propensity for the development of drug-resistant mutants. We will address this hypothesis by exploiting a comprehensive robust multi-step pre-clinical in vitro and in vivo testing platform for novel drug combinations that ranges from HTS screening of unbiased combinations of drugs with known antiviral activities against SARS-CoV-2 and pharmacometrics to ensure potential for human use, to therapeutic efficacy models in SARS-CoV-2-infected well-differentiated primary human airway epithelial cell cultures (WD-PAECs) and animals (Syrian golden hamsters and hACE2 mice) with the most promising combination drug hits. Promising hits will be subjected to antiviral screening against a panel of variants of concern (VOCs) and endogenously circulating coronaviruses to ensure broad activity against SARS-CoV-2 VOCs and the potential for pan-CoV antiviral activities.We will extend this testing platform to non-biased screening of extensive approved drug libraries that have not previously been mined for drug combinations to treat COVID-19 with a view to ensuring a pipeline of future therapies against SARS-CoV-2.It should also be noted that we will make our pipeline available to the UK-CTAP to make recommendations for candidate evaluation. For this, a candidate/combination could enter evaluation at any WP that is appropriate given data that are available at the time.This project will provide comprehensive data to enable robust decision making regarding the entry of combination antiviral drugs hits into the UK COVID-19 clinical trial platforms or the de-prioritisation of drugs from further development.