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

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.