Abstract
Many viruses exploit conserved host components and pathways to support their lifecycles, making host-directed antivirals (HDAs) an attractive broad-spectrum strategy. Fatty acid synthase (FASN) is a central enzyme complex in lipid biosynthesis that catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA. While expressed systemically, FASN activity is highest in liver, adipose, and lactating mammary tissues. Numerous World Health Organization (WHO) priority pathogens belonging to the Coronaviridae, Flaviviridae, Togaviridae, and Orthomyxoviridae families, depend on host lipid metabolism, particularly FASN activity, to sustain infection. Thus, HDAs designed to inhibit FASN are a promising broad-spectrum approach to disrupt the lifecycle and limit the spread of many viruses. FASN is a multi-functional enzyme essential to many cellular processes, such as energy storage, membrane remodelling, and signaling pathways. Although FASN is most well characterized in viral infection to be exploited for its role in lipid droplet formation and replication organelle synthesis, its other mechanistic roles in viral infection remain poorly understood and need to be explored. As well, previous work has focused on FASN inhibition for cancer treatment using orally administered inhibitors, but this work is currently limited to mouse models. Due to the essential role of FASN in host metabolism, inhibition of the enzyme carries a high risk of off-target and cytotoxic effects. Therefore, a major knowledge gap exists in exploring safer ways to design and deliver FASN inhibitors. This study explores the hypothesis that selective and targeted delivery of FASN inhibitors can suppress viral replication while minimizing systemic toxicity. Two key research questions will be addressed, (1) What mechanistic role does FASN play in viral lifecycles beyond replication organelle formation? (2) How can current FASN inhibitors be adapted to minimize off-target and cytotoxic effects? Addressing these questions will inform the development of safer, broad-spectrum antiviral strategies, has implications in cancer treatment, and can improve our pandemic preparedness against emerging and re-emerging viral threats.