Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives

Different isoforms of the Hsp90 chaperone family play distinct roles in diseases encompassing cancer, neurodegeneration, and ischemia. Isoform-selective design of inhibitors of the Hsp90 active site has proven difficult due to its conservation. Recent advances in targeted organelle delivery and rational design have identified compounds that selectively perturb the activity of TRAP1, the mitochondrial Hsp90 isoform that controls metabolism in disease progression. Computational approaches taking both structure and dynamics into account, combined with innovative machine learning strategies for the categorization of the activity of potential allosteric hits, can lead to more potent and specific TRAP1 compounds. Highly specific molecules targeting TRAP1 are promising leads for a detailed comprehension of its functions and for drawing innovative therapeutic strategies. 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. 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.