Synthesis Of Molecular Probes For Cystic Fibrosis Research
thesisposted on 2021-06-08, 11:57 authored by Bashar Alkhouri
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.