Cystic fibrosis is the most common genetically inherited disease to affect Caucasians. Despite major breakthroughs in the 1990's resulting in the identification of mutations in the chloride channel CFTR as the cause of disease both in the airway and the intestine as well as other epithelia, progress towards an effective treatment has been disappointing. Greatest hope lies with the identification of molecules able to activate CFTR rather than gene therapy (for example click here for free access to our recent dossier "Novel activators of CFTR"). UCSF researchers have recently addressed this challenge by assaying a collection of 60,000 diverse drug-like compounds for CFTR activating properties. Primary screening yielded 57 strong activators, most of which were unrelated in chemical structure to known CFTR activators, and 284 weaker activators. Secondary analysis of the strong activators included analysis of CFTR specificity, forskolin requirement, transepithelial short-circuit current, activation kinetics, dose response, toxicity, and activation mechanism. Three compounds, the most potent being a dihydroisoquinoline, activated CFTR by elevating cellular cAMP, probably by phosphodiesterase inhibition. Fourteen compounds activated CFTR without cAMP elevation or phosphatase inhibition, suggesting direct CFTR interaction. The most potent compounds had tetrahydrocarbazol, hydroxycoumarin, and thiazolidine core structures. These compounds induced CFTR Cl(-) currents rapidly and with nanomolar potency and were CFTR-selective, reversible, and nontoxic. The deletion of three nucleotides from the CFTR gene causes the deletion of phenylalanine at position 508 of CFTR and accounts for the majority of cases of cystic fibrosis (Δ508). This mutation causes a defect in trafficking so that CFTR does not reach the plasma membrane and is instead degraded. This defect can be treated by fatty acids that increase membrane cycling of CFTR. However, even when trafficking defects have been overcome, Δ508 CFTR activation remains attenuated. Therefore therapies able to enhance the activation as well as trafficking of Δ508 CFTR are likely to have considerable therapeutic benefit. Perhaps of greater importance to the present study therefore are findings that after correction of trafficking, the tetrahydrocarbazol and N-phenyltriazine derivatives selected by the UCSF group strongly stimulated Cl(-) conductance with sub-micromolar potency. The new activators identified here may be useful in defining molecular mechanisms of CFTR activation and as lead compounds in CF drug development.

Entry date October, 2002

Adapted from Ma et al, J Biol Chem 2002 Oct 4;277(40):37235-41

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