Submitted on February 4, 2008
Accepted on May 26, 2008
Chemical conjugation of 
F508-CFTR corrector deoxyspergualin to transporter human serum albumin enhances its ability to rescue Cl- channel functions
Caroline Norez1, Matteo Pasetto2, Maria Cristina Dechecchi3, Erika Barison2, Cristina Anselmi2, Anna Tamanini3, Federica Quiri3, Luigi Cattel4, Paolo Rizzotti3, Franco Dosio4, Giulio Cabrini3, and Marco Colombatti2*
1 Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, University Hospital of Verona, Verona, Italy
2 Pathology, University of Verona, Verona, Italy
3 Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Hematology, University Hospital of Verona, Verona, Italy
4 Department of Science and Technology of Medicines, University of Turin, Turin, Italy
* To whom correspondence should be addressed. E-mail: marco.colombatti{at}univr.it.
The most common mutation of the Cystic Fibrosis (CF) gene, the deletion of Phe508, encodes a protein (
F508-CFTR) which fails to fold properly, thus mutated F508-Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is recognized and degraded via the ubiquitin-proteasome endoplasmic reticulum (ER)-associated degradation pathway (ERAD).
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 have been proposed as having potential utility in F508-CFTR are those targeting 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 disulphide-based cross-linker and its administration to cells carrying F508-CFTR resulted in a greater enhancement of 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.
