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中起着重要作用，这是开发具有新机制的药物的方向。在不断变化的环境条件下，分子伴侣通过与其客户蛋白质之间广泛的蛋白质-蛋白质相互作用（PPI），在调节蛋白质命运决定和蛋白质稳态方面发挥着重要的生物学功能。借助分子伴侣机，可以适当地安排蛋白质折叠，运输，质量控制和客户蛋白质降解的过程。分子伴侣的核心成员，包括热休克蛋白（HSP）家族及其共伴侣，由于它们涉及多种疾病，因此正在成为潜在的药物靶标。小分子调节剂的开发不仅针对分子伴侣本身，而且还针对分子伴侣，伴侣伴侣和客户中的PPI，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以及更广泛疾病的潜在候选药物的化学工具。在这里，我们审查了分子伴侣机制热休克蛋白及其共同伴侣蛋白的关键检查点，以讨论针对它们的小分子对蛋白质命运决定的调节。