Chairs: Aoife Mulry and David Mark

In the last 20 years three pandemic coronaviruses have emerged, with many more coronaviruses circulating in animal reservoirs, viral emergence is likely. There is a need for broad-spectrum antivirals which can be deployed in response to emerging viruses. Plant extracts have been used around the world for medicinal purposes and are a rich source of novel antiviral compounds. We evaluated a panel of compounds and synthetic xanthones based on Swerita bioactive compounds for antiviral activity against human coronaviruses HCoV-OC43 and HCov-229E. Infected cell lines were treated with the compounds, and impact on infectivity assessed by quantifying viral titres. We identified six natural product compounds displaying antiviral activity at non-cytotoxic concentrations, with potential broad-spectrum activity demonstrated across two model coronaviruses . Although synthetic xanthones significantly reduced viral infectivity, their potency was lower than that of the natural xanthone mangiferin, which showed a ≥3 log10 reduction in infectivity. The additional structural complexity of mangiferin and other natural xanthones may contribute to their enhanced antiviral efficacy. Mechanism of action studies suggests that the hit compounds inhibit the virus at early stages in the viral lifecycle. However, the compounds do not show inhibition of spike pseudo-typed lentivirus infection, showing that spike-mediated entry is unlikely to be the inhibitory mechanism. Our preliminary data indicate potential inhibition of the viral main protease, and further studies are underway to confirm this target. This work provides insights into the potential for identifying and modifying natural compounds, offering a promising pathway towards new pan-coronavirus antiviral development.