Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
| Autor: | Amal Ting, Abby Sewell, Cecilia Pena-Rasgado, Dominic Picarella, Antonio E. Lacerda, Maisy Yeager, Chi B. Vu, Chandran Sachin, Pallavi Lonkar, Robert J. Bridges, A. Nichols, Curtis Bordwell, Feng Liu, Allison Wensley |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein Folding Cysteamine Cystic Fibrosis Transmembrane Conductance Regulator Ivacaftor 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery medicine Autophagy chemistry.chemical_classification biology Lumacaftor Fatty Acids Fatty acid Potentiator Cystic fibrosis transmembrane conductance regulator 030104 developmental biology chemistry Biochemistry 030220 oncology & carcinogenesis biology.protein Molecular Medicine medicine.drug Conjugate |
| Zdroj: | Journal of medicinal chemistry. 60(1) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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