LAUSR

The mosquito protein AEG12 encompasses a large (~ 3800 Å3) hydrophobic cavity which binds and delivers unsaturated fatty acids into biological membranes, allowing it to lyse cells and neutralize a wide range of enveloped viruses. Herein, the lytic and antiviral activities are modified with non‐naturally occurring lipid ligands. We generated novel AEG12 complexes in which the endogenous fatty acid ligands were replaced with hydrophobic viral inhibitors. The resulting compounds modulated cytotoxicity and infectivity against SARS‐CoV‐2, potentially reflecting additional mechanisms of action beyond membrane destabilization. These studies provide valuable insight into the design of novel broad‐spectrum antiviral therapeutics centred on the AEG12 protein scaffold as a delivery vehicle for hydrophobic therapeutic compounds.