The Synthesis of Molecular Probes Based on Cystic Fibrosis Drugs for Biological Research

Cystic fibrosis (CF) is a genetic disorder caused by a mutation in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations either impair trafficking to thecell membrane, reducefunction as ananion channel,orboth. Ivacaftor(a channel potentiator) was the first FDA-approved drug that treats the underlying cause of CF, specifically for patients with the G551D mutation. Shortly after, Orkambi, a combination of ivacaftor and the trafficking corrector lumacaftor was FDA-approved for patients homozygous for the F508del mutation. Based onclinical studies, itisreportedthatOrkambi has amodesteffect onlung function due to the negative impact of ivacaftor on the stability of F508del CFTR. Ivacaftor and lumacaftor were discovered and optimized through functional bioassays, and their interaction at the molecular level is not fully understood. To better understand the drug-protein interaction and inform the development of better CF drugs, molecular probes have been synthesized based on the structures of ivacaftor and lumacaftor.