Pharmacological chaperoning: a primer on mechanism and pharmacology.
Pharmacological chaperoning: a primer on mechanism and pharmacology.
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DOI：
10.1016/j.phrs.2014.01.005
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发表时间：
2014-05
影响因子：
9.3
通讯作者：
Ryder KG
中科院分区：
文献类型：
--
作者：
Leidenheimer NJ;Ryder KG
大约40%的疾病可归因于蛋白质错误折叠，包括那些基因突变产生错误折叠突变的疾病。有趣的是，许多这些突变体并没有最终错误折叠，因为像天然折叠一样，随后的运输到功能位置，可以由靶向性的小分子诱导，这些小分子被称为药理学伴侣、药辅酮或药理学伴侣（PCs）。PC靶标包括酶、受体、转运体和离子通道，揭示了配体辅助折叠可参与的蛋白质的广度。本文综述的目的是提供一个完整的入门介绍不同的机制和药理的PCs。在这方面，我们研究了PC拯救错误折叠突变体的结构机制，包括PC作为有缺陷的分子内相互作用的替代品的能力，以及在分子间水平上克服寡聚化缺陷和显性负面效应的能力，以及影响异戊二聚受体的亚基化学计量学。不足为奇的是，pc介导的错误折叠突变体的结构纠正使参与蛋白质质量控制和前向运输的分子伴侣的相互作用正常化。各种小分子已被证明是有效的pc，并考虑了使用直立拮抗剂、活性位点抑制剂、直立激动剂和变构调节剂pc的优缺点。还研究了几种治疗药物可能具有未被识别的pc活性的可能性，这种伴随活性可能介导/促成治疗作用和/或解释不良反应。最后，我们探讨了药物陪伴利用内在配体辅助折叠机制的证据。鉴于PC拯救与蛋白质折叠紊乱相关的突变体的广泛适用性，无论是在体外还是在体内，PC的治疗潜力是巨大的。这在溶酶体贮积症、囊性纤维化和肾源性尿崩症的治疗中最为明显，其原理已在人类中得到证实。
Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs is considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast. This is most evident in the treatment of lysosomal storage disorders, cystic fibrosis, and nephrogenic diabetes insipidus, for which proof of principle in humans has been demonstrated.