Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis.
Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis.
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DOI：
10.2174/13816128113199990318
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发表时间：
2013-05
影响因子：
3.1
通讯作者：
M. Amaral;C. Farinha
中科院分区：
文献类型：
--
作者：
M. Amaral;C. Farinha
最近越来越多的囊性纤维化（CF）药物发现计划的目标是用小分子化合物纠正突变CFTR的多个缺陷。然而，这些分子恢复突变CFTR的作用机制（MoA）仍然知之甚少，特别是CFTR校正剂，即拯救CF患者中最常见突变体的细胞表面的化合物——F508del-CFTR。然而，越来越多的证据表明，为了完全修复与 F508del-CFTR 相关的多种缺陷，可能需要具有不同矫正特性的不同小分子。为了实现这一目标，需要更好地了解校正器的 MoA，并且应该解决一些限制。实现这一目标的方法包括：1）测试化合物与其他（非药理学）拯救策略（例如回复体或低温）的综合效果； 2) 评估多种细胞模型的效果（非上皮细胞与上皮细胞、非人类与人类、永生化与原代培养物、极化与非极化、细胞与组织）； 3) 评估化合物对分离的 CFTR 结构域的影响（例如，通过表面等离子共振进行化合物结合，评估对结构域折叠和聚集的影响）；最后 4) 评估化合物在拯救不同 CFTR 突变体和其他突变蛋白方面的特异性。本文对这些主题进行回顾和讨论，以便就如何结合多种拯救突变 CFTR 的方法来为 CF 患者带来最终利益提供最先进的回顾。
Correcting multiple defects of mutant CFTR with small molecule compounds has been the goal of an increasing number of recent Cystic Fibrosis (CF) drug discovery programmes. However, the mechanism of action (MoA) by which these molecules restore mutant CFTR is still poorly understood, in particular of CFTR correctors, i.e., compounds rescuing to the cells surface the most prevalent mutant in CF patients--F508del-CFTR. However, there is increasing evidence that to fully restore the multiple defects associated with F508del-CFTR, different small molecules with distinct corrective properties may be required. Towards this goal, a better insight into MoA of correctors is needed and several constraints should be addressed. The methodological approaches to achieve this include: 1) testing the combined effect of compounds with that of other (non-pharmacological) rescuing strategies (e.g., revertants or low temperature); 2) assessing effects in multiple cellular models (non-epithelial vs epithelial, non-human vs human, immortalized vs primary cultures, polarized vs non polarized, cells vs tissues); 3) assessing compound effects on isolated CFTR domains (e.g., compound binding by surface plasmon resonance, assessing effects on domain folding and aggregation); and finally 4) assessing compounds specificity in rescuing different CFTR mutants and other mutant proteins. These topics are reviewed and discussed here so as to provide a state-of-the art review on how to combine multiple ways of rescuing mutant CFTR to the ultimate benefit of CF patients.