Design and synthesis of a hybrid potentiator-corrector agonist of the cystic fibrosis mutant protein ΔF508-CFTR

被引:23
|
作者
Mills, Aaron D. [1 ,2 ,3 ,4 ]
Yoo, Choong [1 ]
Butler, Jeffrey D. [1 ]
Yang, Baoxue [2 ,3 ]
Verkman, A. S. [2 ,3 ]
Kurth, Mark J. [1 ]
机构
[1] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA
[4] Univ Idaho, Dept Chem, Moscow, ID 83844 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
Cystic fibrosis transmembrane conductance regulator protein (CFTR); Delta F508-CFTR; Potentiators; Correctors; Hybrids; Multi-ligand drug; TRANSMEMBRANE CONDUCTANCE REGULATOR; SMALL-MOLECULE CORRECTORS; CFTR;
D O I
10.1016/j.bmcl.2009.11.020
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A developing therapy of cystic. brosis caused by the Delta F508 mutation in CFTR employs correction of defective CFTR chloride channel gating by a 'potentiator' and of defective CFTR protein folding by a 'corrector'. Based on SAR data for phenylglycine-type potentiators and bithiazole correctors, we designed a hybrid molecule incorporating an enzymatic hydrolysable linker to deliver the potentiator (PG01) fragment 2 and the corrector (Corr-4a) fragment 13. The hybrid molecule 14 contained PG01-OH and Corr-4a-linker-CO2H moieties, linked with an ethylene glycol spacer through an ester bond. The potentiator 2 and corrector 13 fragments (after cleavage) had low micromolar potency for restoration of Delta F508-CFTR channel gating and cellular processing, respectively. Cleavage of hybrid molecule 14 by intestinal enzymes under physiological conditions produced the active potentiator 2 and corrector fragments 13, providing proof-of-concept for small-molecule potentiator-corrector hybrids as a single drug therapy for CF caused by the Delta F508 mutation. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:87 / 91
页数:5
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