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.

Chemical conjugation of ΔF508-CFTR corrector deoxyspergualin to transporter human serum albumin enhances its ability to rescue Cl- channel functions.

PASETTO, Matteo;DECHECCHI, MARIACRISTINA;BARISON, Erika;ANSELMI, Cristina;TAMANINI, ANNA;CABRINI, GIULIO;COLOMBATTI, Marco
2008

Abstract

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.
Correctors, Cystic fibrosis, Cystic fibrosis transmembrane conductance regulator, Intracellular activation, Transporter protein
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/325640
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