Synthesis Of Molecular Probes For Cystic Fibrosis Research

Cystic fibrosis (CF) is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In healthy individuals, CFTR acts as a phosphorylation and nucleotide regulated channel which mediates the flux of chloride ions across the membrane of epithelial cells. The most common genetic lesion is deletion of phenylalanine residue 508 (F508del-CFTR). The mutation leads primarily to misfolding of the protein, resulting in degradation of most of the protein before it reaches the cell membrane. Also, any F508del-CFTR in the membrane exhibits reduced ion channel activity. The drug-like small molecule VRT-532 has been shown to improve both the trafficking of F508del-CFTR to the cell membrane, as well as its channel function. The exact nature of the interaction of VRT-532 with mutant CFTR is not fully understood. The goal of this research is to help reveal the nature of interaction between VRT-532 and mutant CFTR protein by synthesizing derivatives useful in biochemical studies. Understanding the molecular basis for this interaction will provide us with a template for the development of therapeutically efficacious compounds.