Pharmacological effectors of GRP78 chaperone in cancers
Pharmacological effectors of GRP78 chaperone in cancers
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DOI：
10.1016/j.bcp.2019.02.038
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发表时间：
2019-05-01
影响因子：
5.8
通讯作者：
Waring, Michael J.
中科院分区：
文献类型：
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作者：
Bailly, Christian;Waring, Michael J.
蛋白伴侣 GRP78 是内质网 (ER) 功能的主要调节因子，并且经常在癌细胞表面过度表达，从而导致化疗耐药。它代表了一种经过充分研究的 ER 应激标志物，但仍是新药开发中尚未探索的目标。本综述旨在阐明 GRP78 调节剂的结构和功能多样性，涵盖 130 多种天然产物、合成分子、特定肽和针对 GRP78 的单克隆抗体。提出了几种促进 GRP78 或使其失能的方法，包括使用寡核苷酸和通常与细胞毒性有效负载缀合的特定细胞递送肽来设计针对 GRP78 的治疗剂。一系列打开/关闭 GRP78 的药物被公开，包括直接与 GRP78（主要是其 ATP 位点）结合的分子。有许多选择可以正向或负向调节伴侣蛋白的表达，或干扰其细胞运输。这篇综述提供了 GRP78 药理效应子的分子图谱，并增强了 GRP78 阻遏物可能代表有前途的抗癌疗法的观点，特别是在限制癌细胞的化疗耐药性方面。 GRP78 靶向药物在其他治疗方式中的潜力也被激发出来。
The protein chaperone GRP78 is a master regulator of endoplasmic reticulum (ER) functions and is frequently over-expressed at the surface of cancer cells where it contributes to chemo-resistance. It represents a well-studied ER stress marker but an under-explored target for new drug development. This review aims to untangle the structural and functional diversity of GRP78 modulators, covering over 130 natural products, synthetic molecules, specific peptides and monoclonal antibodies that target GRP78. Several approaches to promote or to incapacitate GRP78 are presented, including the use of oligonucleotides and specific cell-delivery peptides often conjugated to cytotoxic payloads to design GRP78-targeted therapeutics. A repertoire of drugs that turn on/off GRP78 is exposed, including molecules which bind directly to GRP78, principally to its ATP site. There exist many options to regulate positively or negatively the expression of the chaperone, or to interfere with its cellular trafficking. This review provides a molecular cartography of GRP78 pharmacological effectors and adds weight to the notion that GRP78 repressors could represent promising anticancer therapeutics, notably as regards limiting chemo-resistance of cancer cells. The potential of GRP78-targeting drugs in other therapeutic modalities is also evoked.