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J Med Chem. 2017 Jan 12;60(1):458-473. doi: 10.1021/acs.jmedchem.6b01539. Epub 2016 Dec 23.

Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Author information

1
Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
2
Chicago Medical School, Rosalind Franklin University of Medicine and Science , 3333 Green Bay Road, North Chicago, Illinois 60064, United States.
3
Charles River Laboratories , 14656 Neo Parkway, Cleveland, Ohio 44128, United States.

Abstract

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.

PMID:
27976892
DOI:
10.1021/acs.jmedchem.6b01539
[Indexed for MEDLINE]

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