TY - JOUR
T1 - Pharmacological correctors of mutant CFTR mistrafficking
AU - Pedemonte, Nicoletta
AU - Galietta, Luis J V
PY - 2012
Y1 - 2012
N2 - The lack of phenylalanine 508 (ΔF508 mutation) in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) Cl- channel represents the most frequent cause of CF, a genetic disease affecting multiple organs such as lung, pancreas, and liver. ΔF508 causes instability and misfolding of CFTR protein leading to early degradation in the endoplasmic reticulum and accelerated removal from the plasma membrane. Pharmacological correc-tors of mutant CFTR protein have been identified by high-throughput screening of large chemical libraries, by in silico docking of virtual compounds on CFTR structure models, or by using compounds that affect the whole proteome (e.g., histone deacetylase inhibitors) or a single CFTR-interacting protein. The presence of multiple defects of the CFTR pro-tein caused by the ΔF508 mutation and the redundancy of quality control mechanisms detecting ΔF508-CFTR as a defective protein impose a ceiling to the maximal effect that a single compound (corrector) may obtain. Therefore, treatment of patients with the most frequent CF mutation may require the optimized combination of two drugs having additive or synergic effects.
AB - The lack of phenylalanine 508 (ΔF508 mutation) in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) Cl- channel represents the most frequent cause of CF, a genetic disease affecting multiple organs such as lung, pancreas, and liver. ΔF508 causes instability and misfolding of CFTR protein leading to early degradation in the endoplasmic reticulum and accelerated removal from the plasma membrane. Pharmacological correc-tors of mutant CFTR protein have been identified by high-throughput screening of large chemical libraries, by in silico docking of virtual compounds on CFTR structure models, or by using compounds that affect the whole proteome (e.g., histone deacetylase inhibitors) or a single CFTR-interacting protein. The presence of multiple defects of the CFTR pro-tein caused by the ΔF508 mutation and the redundancy of quality control mechanisms detecting ΔF508-CFTR as a defective protein impose a ceiling to the maximal effect that a single compound (corrector) may obtain. Therefore, treatment of patients with the most frequent CF mutation may require the optimized combination of two drugs having additive or synergic effects.
KW - CFTR
KW - Chloride channel
KW - Cystic fibrosis
KW - Drug discovery
KW - Trafficking defect
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U2 - 10.3389/fphar.2012.00175
DO - 10.3389/fphar.2012.00175
M3 - Article
C2 - 23060795
AN - SCOPUS:84870735685
VL - 3 OCT
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
M1 - Article 175
ER -