Meng Qianli, Li Bingbing X, Xiao Xiangshu
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, United States.
Front Mol Biosci. 2018 Apr 20;5:35. doi: 10.3389/fmolb.2018.00035. eCollection 2018.
The 60 kDa heat shock protein (Hsp60) is classically known as a mitochondrial chaperonin protein working together with co-chaperonin 10 kDa heat shock protein (Hsp10). This chaperonin complex is essential for folding proteins newly imported into mitochondria. However, Hsp60, and/or Hsp10 have also been shown to reside in other subcellular compartments including extracellular space, cytosol, and nucleus. The proteins in these extra-mitochondrial compartments may possess a wide range of functions dependent or independent of its chaperoning activity. But the mechanistic details remain unknown. Mutations in gene have been shown to be associated with neurodegenerative disorders. Abnormality in expression level and/or subcellular localization have also been detected from different diseased tissues including inflammatory diseases and various cancers. Therefore, there is a strong interest in developing small molecule modulators of Hsp60. Most of the reported inhibitors were discovered through various chemoproteomics strategies. In this review, we will describe the recent progress in this area with reported inhibitors from both natural products and synthetic compounds. The former includes mizoribine, epolactaene, myrtucommulone, stephacidin B, and avrainvillamide while the latter includes -carboranylphenoxyacetanilides and gold (III) porphyrins. The potencies of the known inhibitors range from low micromolar to millimolar concentrations. The potential applications of these inhibitors include anti-cancer, anti-inflammatory diseases, and anti-autoimmune diseases.
60 kDa热休克蛋白（Hsp60）传统上被认为是一种线粒体伴侣蛋白，与10 kDa共伴侣热休克蛋白（Hsp10）协同工作。这种伴侣蛋白复合物对于新导入线粒体的蛋白质折叠至关重要。然而，Hsp60和/或Hsp10也已被证明存在于其他亚细胞区室中，包括细胞外空间、细胞质和细胞核。这些线粒体外部区室中的蛋白质可能具有广泛的功能，取决于或独立于其伴侣活性。但其机制细节仍不清楚。基因中的突变已被证明与神经退行性疾病有关。在包括炎症性疾病和各种癌症在内的不同患病组织中也检测到表达水平和/或亚细胞定位异常。因此，人们对开发Hsp60的小分子调节剂有着浓厚的兴趣。大多数报道的抑制剂是通过各种化学蛋白质组学策略发现的。在这篇综述中，我们将描述该领域的最新进展，包括来自天然产物和合成化合物的报道抑制剂。前者包括咪唑立宾、表乳糖菌素、桃金娘烯酮、千金藤定碱B和阿夫拉文酰胺，而后者包括β-碳硼烷基苯氧基乙酰苯胺和金（III）卟啉。已知抑制剂的效力范围从低微摩尔到毫摩尔浓度。这些抑制剂的潜在应用包括抗癌、抗炎性疾病和抗自身免疫性疾病。
