Wang Lei, Xu Xiaoli, Jiang Zhengyu, You Qidong
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharm Sin B. 2020 Oct;10(10):1904-1925. doi: 10.1016/j.apsb.2020.01.018. Epub 2020 Feb 7.
Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
蛋白质命运决定和蛋白质稳态的调节在改变蛋白质水平方面起着重要作用，这为开发具有新机制的药物提供了方向。分子伴侣通过与它们的客户蛋白广泛的蛋白质-蛋白质相互作用（PPI），在不断变化的环境条件下对蛋白质命运决定和蛋白质稳态的调节发挥着重要的生物学功能。在分子伴侣机制的帮助下，客户蛋白的蛋白质折叠、运输、质量控制和降解过程能够得到妥善安排。分子伴侣的核心成员，包括热休克蛋白（HSP）家族及其共伴侣，正成为潜在的药物靶点，因为它们参与了众多疾病状态。开发不仅靶向伴侣蛋白本身，而且靶向伴侣蛋白、共伴侣和客户蛋白之间PPI的小分子调节剂正越来越受到关注。这些调节剂被广泛用作研究伴侣蛋白网络的化学工具以及针对更广泛疾病的潜在候选药物。在此，我们综述了分子伴侣机制HSP及其共伴侣的关键检查点，以讨论靶向它们的小分子对蛋白质命运决定的调节作用。
