Zheng Jianfei, Hashimoto Atsushi, Putnam Marc, Miller Katherine, Koh John T
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Bioconjug Chem. 2008 Jun;19(6):1227-34. doi: 10.1021/bc8000326. Epub 2008 May 29.
Molecular conjugates of hormone receptor-ligands with molecular probes or functional domains are finding diverse applications in chemical biology. Whereas many examples of hormone conjugates that target steroid hormone receptors have been reported, practical ligand conjugates that target the nuclear thyroid hormone receptor (TRbeta) are lacking. TR-targeting conjugate scaffolds based on the ligands GC-1 and NH-2 and the natural ligand triiodothyronine (T3) were synthesized and evaluated in vitro and in cellular assays. Whereas the T3 or GC-1 based conjugates did not bind TRbeta with high affinity, the NH-2 inspired fluorescein-conjugate JZ01 showed low nanomolar affinity for TRbeta and could be used as a nonradiometric probe for ligand binding. A related analogue JZ07 was a potent TR antagonist that is 13-fold selective for TRbeta over TRalpha. JZ01 localizes in the nuclei of TRbeta expressing cells and may serve as a prototype for other TR-targeting conjugates.
激素受体 - 配体与分子探针或功能域的分子缀合物在化学生物学中有着广泛的应用。虽然已经报道了许多靶向类固醇激素受体的激素缀合物实例，但缺乏靶向核甲状腺激素受体（TRβ）的实用配体缀合物。基于配体GC - 1和NH - 2以及天然配体三碘甲状腺原氨酸（T3）合成了靶向TR的缀合物支架，并在体外和细胞试验中进行了评估。虽然基于T3或GC - 1的缀合物没有以高亲和力结合TRβ，但受NH - 2启发的荧光素缀合物JZ01对TRβ表现出低纳摩尔亲和力，可作为配体结合的非放射性探针。相关类似物JZ07是一种有效的TR拮抗剂，对TRβ的选择性比对TRα高13倍。JZ01定位于表达TRβ的细胞的细胞核中，可作为其他靶向TR的缀合物的原型。
