Development of Novel PCSK9 Inhibitors as Potential Broad-Spectrum Antivirals

PCSK9 is a key drug target for hypercholesterolemia-related cardiovascular diseases. Beyond this primary role, emerging evidence indicates its implication in other pathologies, including neurodegenerative disorders, cancer, and infections. In viral infections, PCSK9 inhibitors offer a promising host-targeted therapeutic strategy due to their lipid-lowering effects. Notably, altered PCSK9 levels are observed during viral infections, such as those caused by Flaviviruses, Retroviruses, and Coronaviruses. No small-molecule PCSK9 inhibitors (PCSK9i) have been approved to date, offering a unique drug discovery opportunity. Recently our research group has identified a novel class of PCSK9i characterized by a 4-amino-2-pyridone chemotype. The early lead compound from the first-generation inhibitors exhibited excellent in vitro anti-PCSK9 activity and in vivo tolerability. To further optimize its proprieties, a chemistry-driven late-stage functionalization (LSF) strategy has been employed to modify the predicted metabolic "soft spots." Electrochemistry (EC), multicomponent reaction (MCR), and microwave-assisted (MW) protocols were established as key tools for generating new PCSK9i. This sustainable medicinal chemistry campaign successfully identified new candidates with improved metabolic stability and potent PCSK9 inhibition. Beyond the extensive data on PCSK9, preliminary findings from antiviral testing revealed significant activity against Flaviviruses, Poxviruses, and Coronaviruses, highlighting the potential of our 4-amino-2-pyridone as innovative broad-spectrum antiviral agents.