Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
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- 作者：Chi B. VuRobert J. Bridges ; Cecilia Pena-Rasgado ; Antonio E. Lacerda ; Curtis Bordwell ; Abby Sewell ; Andrew J. Nichols ; Sachin Chandran ; Pallavi Lonkar ; Dominic Picarella ; Amal Ting ; Allison Wensley ; Maisy Yeager ; Feng Liu
- 刊名：Journal of Medicinal Chemistry
- 出版年：2017
- 出版时间：January 12, 2017
- 年：2017
- 卷：60
- 期：1
- 页码：458-473
- 全文大小：794K
- ISSN：1520-4804
文摘
A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.