F508del-cystic fibrosis transmembrane regulator correctors for treatment of cystic fibrosis: a patent review
F508del-cystic fibrosis transmembrane regulator correctors for treatment of cystic fibrosis: a patent review
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DOI：
10.1517/13543776.2015.1045878
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发表时间：
2015-08
影响因子：
6.6
通讯作者：
Hong Yang;T. Ma
中科院分区：
文献类型：
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作者：
Hong Yang;T. Ma
前言：囊性纤维化是一种常染色体隐性遗传病，由囊性纤维化跨膜调节因子功能障碍引起。508位苯丙氨酸缺失(F508del)是CFTR中最常见的导致细胞加工、氯通道门控和蛋白质稳定性缺陷的突变。F508del-CFTR的药理调节剂旨在纠正CFTR蛋白中的细胞加工缺陷(校正子)和门控缺陷(增强子)，被认为是治疗CF病的有前途的药物。寻找F508del-CFTR调节剂的努力已经显示出令人鼓舞的结果，几种小分子化合物已经进入临床试验，甚至代表了临床选择。涉及的领域：这篇综述涵盖了专利(2005年至今)和科学文献中描述的F508del-CFTR校正器的发现。专家观点：CFTR校正剂的环丙烷甲酰胺类化合物在这一领域继续占据主导地位，其中Lumacaftor(一种NBD1-MSD1/2界面稳定剂)是最有前途的化合物，目前正处于美国FDA的优先审查之下。然而，异丙肾上腺素(增强剂)对空腔效应的消除作用表明，需要发现新的能够很好地配合的校正和增强剂。同时确定校正剂(特别是NBD1稳定剂)和增效剂组合的综合筛查应提供一种替代策略。最近报道的天然产物组分文库可能对整合筛选有用。
Introduction: Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylalanine at residue 508 (F508del) is the most common mutation that causes cellular processing, chloride channel gating and protein stability defects in CFTR. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. Endeavors in searching F508del-CFTR modulators have shown encouraging results, with several small-molecule compounds having entered clinical trials or even represented clinical options. Areas covered: This review covers the discovery of F508del-CFTR correctors described in both patents (2005 – present) and scientific literatures. Expert opinion: Cyclopropane carboxamide derivatives of CFTR correctors continue to dominate in this area, among which lumacaftor (a NBD1-MSD1/2 interface stabilizer) is the most promising compound and is now under the priority review by US FDA. However, the abrogation effect of ivacaftor (potentiator) on lumacaftor suggests the requirement of discovering new correctors and potentiators that can cooperate well. Integration screening for simultaneously identifying combinations of correctors (particularly NBD1 stabilizer) and potentiators should provide an alternative strategy. A recently reported natural product fraction library may be useful for the integration screening.