Functional fluorescently labeled bithiazole ΔF508-CFTR corrector imaged in whole body slices in mice.
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.
Department of Chemistry, University of California, Davis, Davis, California 95616, United States.
Holly R
HR
Davison
Stephanie
S
Taylor
Chris
C
Drake
Puay-Wah
PW
Phuan
Nico
N
Derichs
Chenjuan
C
Yao
Ella F
EF
Jones
Julie
J
Sutcliffe
A S
AS
Verkman
Mark J
MJ
Kurth
D000818:Animals; D001896:Boron Compounds / Q000737:chemistry*; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000032:analysis* / Q000235:genetics; D005456:Fluorescent Dyes / Q000737:chemistry*; D051379:Mice; D009154:Mutation; D013844:Thiazoles / Q000737:chemistry*; D051598:Whole Body Imaging
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D005456:Fluorescent Dyes; D013844:Thiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator