Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery.
Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery.
复制标题
小分子调节蛋白质命运决定：靶向分子伴侣机制
DOI：
10.1016/j.apsb.2020.01.018
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
You Q
中科院分区：
文献类型：
--
作者：
Wang L;Xu X;Jiang Z;You Q
调节蛋白质命运决定和蛋白质稳态在改变蛋白质水平方面起着重要作用，这是开发具有新机制药物的方向。分子伴侣在不断变化的环境条件下通过与其客户蛋白的广泛的蛋白质-蛋白质相互作用（PPI）调节蛋白质命运决定和蛋白质稳态方面发挥重要的生物学功能。在分子伴侣机制的帮助下，蛋白质的折叠、运输、质量控制和客户蛋白的降解过程可以被合理地安排。分子伴侣的核心成员，包括热休克蛋白（HSPs）家族及其辅助分子伴侣，正成为潜在的药物靶点，因为它们参与了许多疾病。不仅针对分子伴侣本身，而且针对分子伴侣、辅助分子伴侣和客户之间的PPI的小分子调节剂的开发正引起越来越多的关注。这些调节剂被广泛用作研究分子伴侣网络的化学工具以及用于更广泛疾病的潜在候选药物。本文综述了热休克蛋白及其辅助分子伴侣的分子伴侣机制，探讨了以其为靶点的小分子对蛋白质命运决定的调控作用。本文综述了近年来小分子对分子伴侣调控的研究进展，重点介绍了小分子调控蛋白质命运的综合策略和不同机制。
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. This review summarizes the current states on modulation of molecular chaperone by small molecules, focusing on the protein fate decision by comprehensive strategies and different mechanisms.
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