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

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.