Synthesis and Characterization of a Photoaffinity Labelling Probe Based on the Structure of the Cystic Fibrosis Drug Ivacaftor

Resource type
Date created
2018-06-15
Authors/Contributors
Abstract
Cystic Fibrosis (CF) is a genetic disorder caused by loss-of-function mutations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Ivacaftor (1) was the first therapeutic approved for the treatment of CF that is able to restore gating activity to certain CFTR variants although the mechanism of action is poorly understood. Herein we describe the synthesis of a photoaffinity labelling (PAL) probe (2) based on the structure of ivacaftor incorporating a photoreactive diazirine moiety for use in labelling studies designed to identify the binding site for ivacaftor on mutant CFTR. The PAL probe 2 retained potentiation activity, with a potency similar to 1, using a Fluorescent Imaging Plate Reader (FLIPR®) assay measuring ion conductance potentiation of wild type (Wt)-CFTR. Photolabelling experiments with human serum albumin (HSA) as a model protein have shown that probe 2 can label HAS in a manner consistent with observed and predicted binding.
Document
Description
The full text of this paper will be available in June 2019 in keeping with the 12 month embargo period of the journal Tetrahedron. If you need access to the full text prior to June 2019 please contact summit@sfu.ca.
Identifier
DOI: 10.1016/j.tet.2018.06.016
Published as
Hamilton, C. M., Hung, M., Chen, G., Qureshi, Z. & Thompson, J. R., Sun, B., Bear, C. E., Young, R. N.(2018). Synthesis and characterization of a photoaffinity labelling probe based on the structure of the cystic fibrosis drug ivacaftor. Tetrahedron. 10.1016/j.tet.2018.06.016.
Publication title
Tetrahedron
Document title
Synthesis and Characterization of a Photoaffinity Labelling Probe Based on the Structure of the Cystic Fibrosis Drug Ivacaftor
Date
2018
Publisher DOI
10.1016/j.tet.2018.06.016
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Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
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Young-revised_manuscript_june_8_1.pdf 1.22 MB