High-Throughput Synthesis and Evaluation of Antiviral Copolymers for Enveloped Respiratory Viruses

COVID-19 made apparent the devastating impact viral pandemics have had on global health and order. Development of broad-spectrum antivirals to provide early protection upon the inevitable emergence of new viral pandemics is critical. In this work, antiviral polymers are discovered using a combination of high-throughput polymer synthesis and antiviral screening, enabling diverse polymer compositions to be explored. Amphipathic polymers, with ionizable tertiary amine groups, are the most potent antivirals, effective against influenza virus and SARS-CoV-2, with minimal cytotoxicity. It is hypothesized that these polymers interact with the viral membrane as they showed no activity against a nonenveloped virus (rhinovirus). The switchable chemistry of the polymers during endosomal acidification was evaluated using lipid monolayers, indicating that a complex synergy between hydrophobicity and ionization drives polymer-membrane interactions. This new high-throughput methodology can be adapted to continue to engineer the potency of the lead candidates or develop antiviral polymers against other emerging viral classes.