Department of Pathology, Life Sciences Institute, University of Michigan, 210 Washtenaw Ave., Ann Arbor, MI 48109-2216, USA.
Curr Pharm Des. 2013;19(3):404-17. doi: 10.2174/138161213804143699.
Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70's interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain-containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, including roles in pro-folding, pro-degradation and pro-trafficking pathways. Thus, a promising strategy may be to block protein- protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to these goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology.
热休克蛋白 70（Hsp70）在蛋白质平衡中发挥着关键作用，是多种疾病的新兴靶点。然而，竞争性抑制 Hsp70 的酶活性已被证明具有挑战性，并且在某些情况下，可能不是重定向 Hsp70 功能的最有效方法。另一种方法是抑制 Hsp70 与重要共伴侣（如 J 蛋白、核苷酸交换因子（NEF）和四肽重复（TPR）结构域蛋白）的相互作用。这些共伴侣通常与 Hsp70 结合并指导其许多不同的细胞活动。已经表明 Hsp70 与共伴侣之间的复合物具有特定的功能，包括在折叠前、降解前和运输前途径中的作用。因此，一种有前途的策略可能是阻断 Hsp70 与其共伴侣之间的蛋白-蛋白相互作用，或针对破坏这些接触的别构位点。这种方法可能会改变 Hsp70 复合物的平衡，重塑蛋白质组，并有可能恢复健康的蛋白质平衡。在这篇综述中，我们讨论了与这些目标相关的具体挑战和机遇。通过将 Hsp70 复合物作为药物靶点进行研究，我们不仅可能开发出新的治疗方法，还可能发现用于理解 Hsp70 生物学的新化学探针。
