Natural products and other inhibitors of F<sub>1</sub>F<sub>O</sub> ATP synthase.
Patel BA, D'Amico TL, Blagg BSJ.
F<sub>1</sub>F<sub>O</sub> ATP synthase is responsible for the production of >95% of all ATP synthesis within the cell. Dysregulation of its expression, activity or localization is linked to various human diseases including cancer, diabetes, and Alzheimer's and Parkinson's disease. In addition, ATP synthase is a novel and viable drug target for the development of antimicrobials as evidenced by bedaquiline, which was approved in 2012 for the treatment of tuberculosis. Historically, natural products have been a rich source of ATP synthase inhibitors that help unravel the role of F<sub>1</sub>F<sub>O</sub> ATP synthase in cellular bioenergetics. During the last decade, new modulators of ATP synthase have been discovered through the isolation of novel natural products as well as through a ligand-based drug design process. In addition, new data has been obtained with regards to the structure and function of ATP synthase under physiological and pathological conditions. Crystal structure studies have provided a significant insight into the rotary function of the enzyme and may provide additional opportunities to design a new generation of inhibitors. This review provides an update on recently discovered ATP synthase modulators as well as an update on existing scaffolds.