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Am J Physiol Lung Cell Mol Physiol 295: L336-L347, 2008. First published May 30, 2008; doi:10.1152/ajplung.00059.2008
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Chemical conjugation of {Delta}F508-CFTR corrector deoxyspergualin to transporter human serum albumin enhances its ability to rescue Cl– channel functions

Caroline Norez,1,4 Matteo Pasetto,2 Maria Cristina Dechecchi,1 Erika Barison,2 Cristina Anselmi,2 Anna Tamanini,1 Federica Quiri,1 Luigi Cattel,3 Paolo Rizzotti,1 Franco Dosio,3 Giulio Cabrini,1,* and Marco Colombatti2,*

1Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Hematology, University Hospital of Verona and 2Department of Pathology, Section of Immunology, University of Verona, Verona; 3Department of Science and Technology of Medicines, University of Turin, Turin, Italy; and 4Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, Poitiers, France

Submitted 4 February 2008 ; accepted in final form 26 May 2008

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 reticulum-associated 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.

cystic fibrosis; cystic fibrosis transmembrane conductance regulator; correctors; transporter protein; intracellular activation


Address for reprint requests and other correspondence: M. Colombatti, Dept. of Pathology, Section of Immunology, Univ. of Verona, c/o Policlinico G. B. Rossi, P.le L.A. Scuro, 10, 37134 Verona, Italy (e-mail: marco.colombatti{at}univr.it)






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