The mammalian SKI complex is a broad-spectrum antiviral drug target that upregulates cellular cholesterol to inhibit viral replication

The COVID-19 pandemic has underscored the need for effective countermeasures to emerging pathogens. Our research builds upon our published data on a novel antiviral compound termed UMB18. We have found UMB18 capable of inhibiting replication of influenza A virus, coronaviruses, and the filoviruses Marburg and Ebola virus, but did not fully define a mechanism of action. Here, we demonstrate that UMB18 exerts antiviral activity by modulating cellular cholesterol levels. By targeting the SKI complex, UMB18 triggers an increase in endogenous cellular cholesterol, which disrupts the fine balance that viruses rely on for efficient infection. We demonstrate that this mechanism inhibits replication of SARS-CoV-2, revealing a previously undescribed host-directed strategy for antiviral intervention. These findings highlight UMB18's potential as a broad-spectrum antiviral agent and pave the way for further research into its mechanism and therapeutic applications, offering a promising avenue for development of antiviral countermeasures to current, novel, and emerging pathogens.