Functional Fluorescently Labeled Bithiazole ΔF508-CFTR Corrector Imaged in Whole Body Slices in Mice
Functional Fluorescently Labeled Bithiazole ΔF508-CFTR Corrector Imaged in Whole Body Slices in Mice
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DOI：
10.1021/bc2004457
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发表时间：
2011-12-01
影响因子：
4.7
通讯作者：
Kurth, Mark J.
中科院分区：
文献类型：
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作者：
Davison, Holly R.;Taylor, Stephanie;Kurth, Mark J.
我们之前报道了基于双噻唑的囊性纤维化CFTR突变体Delta F508-CFTR缺陷细胞加工纠正剂的鉴定和结构活性分析。在这里，我们报道了功能性荧光标记的双噻唑纠正剂的合成和摄取。通过对四种双噻唑类荧光基团偶联物的合成和功能分析，我们发现以双噻唑为基础的BODIPY偶联物5具有较低的微摩尔效能，用于纠正有缺陷的Delta F508-CFTR细胞错误加工，其功效与基准校正剂corr-4a相当。小鼠经静脉给药5，其在肝外组织内稳定数十分钟。全身冷冻切片的荧光成像显示，荧光校正因子5在胃肠道器官中可见较强，在肺和肝脏中较少。我们的研究结果为通过荧光团标记和全身切片的荧光成像来绘制Delta F508-CFTR校正剂的生物分布提供了概念验证。
We previously reported the identification and structure activity analysis of bithiazole-based correctors of defective cellular processing of the cystic fibrosis-causing CFTR mutant, Delta 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 Delta 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 Delta F508-CFTR corrector by fluorophore labeling and fluorescence imaging of whole-body slices.