The search for drugs to treat cystic fibrosis (CF) has to take into account the large number of mutations affecting the gene and the variety of molecular mechanism through which these mutations cause the functional defect. For instance, deletion of phenylalanine at position 508 (DF508), the most frequent mutation (occurring in more than 50-70 % of patients), causes both a severe defect of CFTR protein processing (trafficking defect) and a decrease of its channel activity (gating defect). Recently, we have found that some 1,4-dihydropyridine (DHP) derivatives used to treat hypertension are able to stimulate the activity of DF508- and G551D-CFTR mutants. As DHPs present only a type of activity facilitating CFTR gating, they must be defined as Potentiators. Antihypertensive DHPs act by blocking L-type voltage-dependent Ca++ channels and therefore cause the relaxation of arterial smooth muscle cells. It has been shown that mutant CFTR is activated by DHPs through a mechanism not involving the modulation of Ca++ channels, but the direct interaction with the CFTR protein itself. These findings prompted us to synthesize DHP derivatives in order to study structure-activity relationships on the modulation of the CFTR-dependent anion transport. Now, we are presenting a series of new DHPs bearing in position 4 a furan-2-yl substituent. DHPs were tested on Fisher rat thyroid cells co-expressing DF508-CFTR mutation and a halide-sensitive yellow fluorescent protein. Cells were incubated at 27 °C to lead the mutant CFTR into the plasma membrane, so rescuing the protein from the endoplasmic reticulum. The tested compounds presented a significant degree of potency against rescued DF508-CFTR. The best activity was found when R = CH2C6H5, R1= H, R2=H, R3= C6H5. Studies of Molecular Modeling on DHPs are in progress: our preliminary data show that DHPs lay into a channel near to the ATP pocket in NBD1 of CFTR (Figure 2): the presence of Potentiators in this site could make more difficult the hydrolysis of ATP, having as a consequence a longer opening time of the CFTR channel.

4-(Furan-2'-yl)-1,4-dihydropyridine derivatives potentiate the CFTR chloride channel

CATENI, FRANCESCA;ZACCHIGNA, MARINA;Drioli, S.;
2010

Abstract

The search for drugs to treat cystic fibrosis (CF) has to take into account the large number of mutations affecting the gene and the variety of molecular mechanism through which these mutations cause the functional defect. For instance, deletion of phenylalanine at position 508 (DF508), the most frequent mutation (occurring in more than 50-70 % of patients), causes both a severe defect of CFTR protein processing (trafficking defect) and a decrease of its channel activity (gating defect). Recently, we have found that some 1,4-dihydropyridine (DHP) derivatives used to treat hypertension are able to stimulate the activity of DF508- and G551D-CFTR mutants. As DHPs present only a type of activity facilitating CFTR gating, they must be defined as Potentiators. Antihypertensive DHPs act by blocking L-type voltage-dependent Ca++ channels and therefore cause the relaxation of arterial smooth muscle cells. It has been shown that mutant CFTR is activated by DHPs through a mechanism not involving the modulation of Ca++ channels, but the direct interaction with the CFTR protein itself. These findings prompted us to synthesize DHP derivatives in order to study structure-activity relationships on the modulation of the CFTR-dependent anion transport. Now, we are presenting a series of new DHPs bearing in position 4 a furan-2-yl substituent. DHPs were tested on Fisher rat thyroid cells co-expressing DF508-CFTR mutation and a halide-sensitive yellow fluorescent protein. Cells were incubated at 27 °C to lead the mutant CFTR into the plasma membrane, so rescuing the protein from the endoplasmic reticulum. The tested compounds presented a significant degree of potency against rescued DF508-CFTR. The best activity was found when R = CH2C6H5, R1= H, R2=H, R3= C6H5. Studies of Molecular Modeling on DHPs are in progress: our preliminary data show that DHPs lay into a channel near to the ATP pocket in NBD1 of CFTR (Figure 2): the presence of Potentiators in this site could make more difficult the hydrolysis of ATP, having as a consequence a longer opening time of the CFTR channel.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2832274
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