Details

Autor(en) / Beteiligte

• Norez, Caroline
• Pasetto, Matteo
• Dechecchi, Maria Cristina
• Barison, Erika
• Anselmi, Cristina
• Tamanini, Anna
• Quiri, Federica
• Cattel, Luigi
• Rizzotti, Paolo
• Dosio, Franco
• Cabrini, Giulio
• Colombatti, Marco

Titel

Chemical conjugation of DeltaF508-CFTR corrector deoxyspergualin to transporter human serum albumin enhances its ability to rescue Cl- channel functions

Ist Teil von

• American journal of physiology. Lung cellular and molecular physiology, 2008-08, Vol.295 (2), p.L336-L347

Ort / Verlag

United States

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• The most common mutation of the cystic fibrosis (CF) gene, the deletion of Phe508, encodes a protein (DeltaF508-CFTR) that fails to fold properly, thus mutated DeltaF508-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 DeltaF508-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 DeltaF508-CFTR resulted in a greater enhancement of DeltaF508-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.