Functional fluorescently labeled bithiazole ΔF508-CFTR corrector imaged in whole body slices in mice

Bioconjug Chem. 2011 Dec 21;22(12):2593-9. doi: 10.1021/bc2004457. Epub 2011 Nov 18.

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, ΔF508-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 ΔF508-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 ΔF508-CFTR corrector by fluorophore labeling and fluorescence imaging of whole-body slices.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Boron Compounds / chemistry*
  • Cystic Fibrosis / diagnosis
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / analysis*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Fluorescent Dyes / chemistry*
  • Mice
  • Mutation
  • Thiazoles / chemistry*
  • Whole Body Imaging*

Substances

  • 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
  • Boron Compounds
  • Fluorescent Dyes
  • Thiazoles
  • Cystic Fibrosis Transmembrane Conductance Regulator