Leidenheimer Nancy J, Ryder Katelyn G
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA 71130-3932, United States.
Pharmacol Res. 2014 May;83:10-9. doi: 10.1016/j.phrs.2014.01.005. Epub 2014 Feb 14.
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 are 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.
大约40%的疾病可归因于蛋白质错误折叠，包括那些由基因突变产生错误折叠突变体的疾病。有趣的是，许多这些突变体并非完全错误折叠，因为通过靶标特异性小分子（可被称为药理伴侣、药物伴侣或药物分子伴侣（PCs））可诱导其形成类似天然的折叠，并随后转运至功能位点。PC的靶标包括酶、受体、转运蛋白和离子通道，这揭示了可通过配体辅助折叠作用的蛋白质的广度。本综述的目的是提供关于PCs多种机制和药理学的综合入门知识。在这方面，我们研究了PCs挽救错误折叠突变体的结构机制，包括PCs作为有缺陷的分子内相互作用替代物的能力，以及在分子间水平上克服寡聚化缺陷和显性负效应，以及影响异五聚体受体亚基化学计量比的能力。不出所料，PC介导的错误折叠突变体的结构校正使与参与蛋白质质量控制和正向转运的分子伴侣的相互作用正常化。已证明多种小分子是有效的PCs，并考虑了使用体位性拮抗剂、活性位点抑制剂、体位性激动剂和变构调节剂PCs的优缺点。还研究了几种治疗药物可能具有未被认识的作为PCs的活性的可能性，并且这种伴侣活性可能介导/促成治疗作用和/或解释不良反应。最后，我们探讨了药理伴侣作用利用内在配体辅助折叠机制的证据。鉴于PCs挽救与蛋白质折叠障碍相关突变体在体外和体内的广泛适用性，PCs的治疗潜力巨大。这在溶酶体贮积症、囊性纤维化和肾性尿崩症的治疗中最为明显，在这些疾病中已在人体中证明了其原理。
