Hsp70 protein complexes as drug targets.
Hsp70 protein complexes as drug targets.
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DOI：
10.2174/138161213804143699
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发表时间：
2013
影响因子：
3.1
通讯作者：
Gestwicki JE
中科院分区：
文献类型：
--
作者：
Assimon VA;Gillies AT;Rauch JN;Gestwicki JE
热休克蛋白 70 (Hsp70) 在蛋白质稳态中发挥着关键作用，是多种疾病的新兴靶标。然而，Hsp70 酶活性的竞争性抑制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 与重要的共伴侣蛋白的相互作用，例如 J 蛋白、核苷酸交换因子 (NEF) 和含有四肽重复 (TPR) 结构域的蛋白。这些共伴侣通常结合 Hsp70 并指导其多种细胞活动。 Hsp70 和共伴侣之间的复合物已被证明具有特定功能，例如促折叠、促降解和促贩运。因此，一种有前途的策略可能是阻断 Hsp70 及其共伴侣之间的蛋白质-蛋白质相互作用，或靶向破坏这些接触的变构位点。这种方法可能会改变 Hsp70 复合物的平衡并重塑蛋白质组，并且有可能恢复健康的蛋白质稳态。在本次审查中，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，我们不仅可以开发用于治疗开发的新先导化合物，还可以发现用于了解 Hsp70 生物学的新化学探针。
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, such as pro-folding, pro-degradation and pro-trafficking. 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 those 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.