Characterization of Small Molecule Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator using Backscattering Interferometry

Cystic Fibrosis (CF) is a genetically-inherited disease characterized by the loss of function of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a chloride ion channel located in the epithelial lining of the lungs and pancreas. CFTR function is reduced or eliminated as the result of a variety of genetic mutations, leading to harmful fluid buildup, decreased organ function, and eventually death. Our goal is to identify and characterize the molecular interactions of several disease-relevant mutations of CFTR with a variety of small molecule modulators of the protein. To this end, we use a highly-sensitive label-free detection method based on backscattering interferometry (BSI). By displaying CFTR in a native membrane environment, we have observed and characterized the interactions of several small molecule modulators, obtaining both binding affinities and structural information about CFTR. This information has allowed us to conclusively determine the previously unknown binding site for one of these modulators.