Functional fluorescently labeled bithiazole ?F508-CFTR corrector imaged in whole body slices in mice.

ABSTRACT: We previously reported the identification and structure-activity analysis of bithiazole-based correctors of defective cellular processing of the cystic fibrosis-causing CFTR mutant, ?F508-CFTR. Here, we report the synthesis and uptake of a functional, fluorescently labeled bithiazole corrector. Following synthesis and functional analysis of four bithiazole-fluorophore conjugates, we found that 5, a bithazole-based BODIPY conjugate, had low micromolar potency for correction of defective ?F508-CFTR cellular misprocessing, with comparable efficacy to benchmark corrector corr-4a. Intravenous administration of 5 to mice established its stability in extrahepatic tissues for tens of minutes. By fluorescence imaging of whole-body frozen slices, fluorescent corrector 5 was visualized strongly in gastrointestinal organs, with less in lung and liver. Our results provide proof-of-concept for mapping the biodistribution of a ?F508-CFTR corrector by fluorophore labeling and fluorescence imaging of whole-body slices.

SUBMITTER: Davison HR 

PROVIDER: S-EPMC3245868 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature