Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives

TRAP1, the mitochondrial isoform of heat shock protein (Hsp)90 chaperones, is a key regulator of metabolism and organelle homeostasis in diverse pathological states. While selective TRAP1 targeting is an attractive goal, classical active-site-directed strategies have proved difficult, due to high active site conservation among Hsp90 paralogs. Here, we discuss advances in developing TRAP1-directed strategies, from lead modification with mitochondria delivery groups to the computational discovery of allosteric sites and ligands. Specifically, we address the unique opportunities that targeting TRAP1 opens up in tackling fundamental questions on its biology and in unveiling new therapeutic approaches. Finally, we show how crucial to this endeavor is our ability to predict the activities of TRAP1-selective allosteric ligands and to optimize target engagement to avoid side effects.