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

SARS-CoV-2 is responsible for the worldwide pandemic that has devasted most countries since it emerged in December 2019. Huge efforts have been made to generate vaccines and drugs to prevent and treat infection, respectively. Vaccine development has proceeded at an unprecendent pace and emergency authorisation was given for a number of vaccines in late 2020 and early 2021. Some drugs have also been shown to have therapeutic benefits against severe COVID-19 disease, most of which are immunemodulators. However, there has been very little success with antiviral therapeutics, with the notable exceptions of remdesivir and monoclonal antibody cocktails. This project, therefore, will seek to bridge this gap and seeks to identify novel drug combinations with enhanced antiviral activities against SARS-CoV-2, the causative agent of COVID-19 disease. We have assembled a very strong team of expertis from Queen's University Belfast, University of Liverpool and University of Oxford. We will initially screen a bespoke library of 140 drugs with known antiviral activity against SARS-CoV-2 for combinations that enhance their antiviral potential. The best combinations will then undergo a robust series of in vitro and in vivo protocols to validate their potential. The data will provide the rationale to make strong recommendations to UK-CTAP for progression to clinical trials. In parallel, we will evaluate the propensity of the drug combinations to elicit drug-resistant mutants, which is an important consideration for drugs that will be used on a massive scale globally. Finally, and in parallel, we have identified 2 large drug libraries that have not been subjected yet to combination drug screening. We will exploit our robust drug screening platform of protocols to identify back-up drug combination candidates to ensure a pipeline of antiviral drugs against SARS-CoV-2 for the future.

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.