Development of a thyroid hormone receptor targeting conjugate.
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.
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Jianfei
J
Zheng
Atsushi
A
Hashimoto
Marc
M
Putnam
Katherine
K
Miller
John T
JT
Koh
D016475:3T3 Cells; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D005452:Fluoresceins / Q000138:chemical synthesis / Q000737:chemistry*; D005454:Fluorescence Polarization; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
D000577:Amides; D001593:Benzyl Compounds; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008024:Ligands; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; C000360:caproamide