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Design and synthesis of photoaffinity labeling probes based on clinically approved CFTR modulators

Resource type
Thesis type
(Thesis) Ph.D.
Date created
2022-08-02
Authors/Contributors
Abstract
Cystic fibrosis (CF) is caused by loss-of-function mutations to the cystic fibrosis transmembrane conductance regulator protein (CFTR). The last decade has seen the development and clinical implementation of small-molecule therapies, termed CFTR modulators, which restore mutant CFTR activity. The CFTR modulators were discovered using functional assays, irrespective of any information of putative binding sites on CFTR. Characterizing the binding sites of the approved CFTR modulators will aid in structure-based drug design of new more effective CFTR treatments. To determine the binding sites of the clinically approved CFTR modulators, photoaffinity labeling (PAL) analogues were designed, synthesized, and characterized. One of the probes based on the structure of ivacaftor has been successfully used in photolabeling studies to identify two binding sites on CFTR. Photolabeling studies utilizing probes based on the structures of lumacaftor and elexacaftor are underway.
Document
Extent
217 pages.
Identifier
etd22066
Copyright statement
Copyright is held by the author(s).
Permissions
This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Supervisor or Senior Supervisor
Thesis advisor: N., Young, Robert
Language
English
Member of collection
Download file Size
etd22066.pdf 7.69 MB

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