Chemical conjugation of Delta F508-CFTR corrector deoxyspergualin to transporter human serum albumin enhances its ability to rescue Cl- channel functions

The most common mutation of the cystic fibrosis (CF) gene, the deletion of Phe508, encodes a protein (Delta F508- CFTR) that fails to fold properly, thus mutated Delta F508- cystic fibrosis transmembrane conductance regulator (CFTR) is recognized and degraded via the ubiquitin- proteasome endoplasmic reticulumassociated degradation pathway. Chemical and pharmacological chaperones and ligand- induced transport open options for designing specific drugs to control protein (mis) folding or transport. A class of compounds that has been proposed as having potential utility in Delta F508- CFTR is that which targets the molecular chaperone and proteasome systems. In this study, we have selected deoxyspergualin (DSG) as a reference molecule for this class of compounds and for ease of cross- linking to human serum albumin (HSA) as a protein transporter. Chemical cross- linking of DSG to HSA via a disulfide-based cross- linker and its administration to cells carrying Delta F508-CFTR resulted in a greater enhancement of Delta F508- CFTR function than when free DSG was used. Function of the selenium- dependent oxidoreductase system was required to allow intracellular activation of HSA- DSG conjugates. The principle that carrier proteins can deliver pharmacological chaperones to cells leading to correction of defective CFTR functions is therefore proven and warrants further investigations.