Dipartimento di Chimica, Università di Pavia. via Taramelli 12, I-27100 Pavia, Italy.
Dipartimento di Scienze Biomediche, Università di Padova, viale G. Colombo 3, I-35131 Padova, Italy.
Trends Pharmacol Sci. 2021 Jul;42(7):566-576. doi: 10.1016/j.tips.2021.04.003. Epub 2021 May 12.
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 是热休克蛋白 (Hsp)90 伴侣的线粒体同工型，是多种病理状态下代谢和细胞器动态平衡的关键调节因子。虽然选择性靶向 TRAP1 是一个有吸引力的目标，但由于 Hsp90 同源物的活性位点高度保守，经典的活性位点定向策略已被证明是困难的。在这里，我们讨论了开发靶向 TRAP1 策略的进展，从带有线粒体传递基团的先导修饰到别构位点和配体的计算发现。具体来说，我们解决了靶向 TRAP1 在解决其生物学基本问题和揭示新的治疗方法方面带来的独特机会。最后，我们展示了在这一努力中，我们预测 TRAP1 选择性别构配体活性和优化靶标结合以避免副作用的能力是多么重要。
