title: Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).
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.
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Chi B
authors.identifier: 0000-0002-6516-8846
authors.initials: CB
authors.lastname: Vu
authors.affiliation: Chicago Medical School, Rosalind Franklin University of Medicine and Science , 3333 Green Bay Road, North Chicago, Illinois 60064, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bridges
authors.affiliation: Chicago Medical School, Rosalind Franklin University of Medicine and Science , 3333 Green Bay Road, North Chicago, Illinois 60064, United States.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Pena-Rasgado
authors.affiliation: Charles River Laboratories , 14656 Neo Parkway, Cleveland, Ohio 44128, United States.
authors.forename: Antonio E
authors.initials: AE
authors.lastname: Lacerda
authors.affiliation: Charles River Laboratories , 14656 Neo Parkway, Cleveland, Ohio 44128, United States.
authors.forename: Curtis
authors.initials: C
authors.lastname: Bordwell
authors.affiliation: Charles River Laboratories , 14656 Neo Parkway, Cleveland, Ohio 44128, United States.
authors.forename: Abby
authors.initials: A
authors.lastname: Sewell
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nichols
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Sachin
authors.initials: S
authors.lastname: Chandran
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Lonkar
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Dominic
authors.initials: D
authors.lastname: Picarella
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Amal
authors.initials: A
authors.lastname: Ting
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Wensley
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Maisy
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D003543:Cysteamine / Q000737:chemistry / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry*; D005227:Fatty Acids / Q000737:chemistry*; D017510:Protein Folding
chemical_list: D005227:Fatty Acids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003543:Cysteamine