Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named “correctors”. So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.
Highlights
Published: 26 February 2021Cystic fibrosis (CF), one of the most frequent genetic diseases [1], is caused by mutations that impair the expression and function of CFTR chloride channel
All compounds were tested in a CFTR corrector assay that is carried out on CFBE41ocells expressing F508del-CFTR
From a structure activity point of view a six atom carbocyle ring, a pivalamide group and a 5-chloro-2-methoxyphenyl carboxamide at the thiazole and pyrrole rings respectively are required for corrector activity
Summary
Cystic fibrosis (CF), one of the most frequent genetic diseases [1], is caused by mutations that impair the expression and function of CFTR chloride channel. VX-809 (Figure 1) [13], known as lumacaftor, the first corrector to be approved for therapeutic use in CF patients, belongs to class 1. It the been first corrector to that be approved for therapeutic use in CFone patients, tocaused class 1.by It has postulated these compounds act by targeting of the belongs problems has been i.e., postulated that these compounds act by targeting of the problems by. Based on our past experience, we decided to investigate the effect on corrector activity of the replacement of one thiazole unit with a pyrrole moiety, which which could could have have allowed allowed the the incorporation of of some somecommon commonstructural structuralfeatures featureswith withconstrained constrained bithiazoles, aiming incorporation bithiazoles, aiming at at the identification of new correctors.
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