A New Small-Molecule Antagonist Inhibits Graves' Disease Antibody Activation of the TSH Receptor
A New Small-Molecule Antagonist Inhibits Graves' Disease Antibody Activation of the TSH Receptor
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DOI：
10.1210/jc.2010-1935
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发表时间：
2011-02-01
影响因子：
5.8
通讯作者：
Gershengorn, Marvin C.
中科院分区：
文献类型：
--
作者：
Neumann, Susanne;Eliseeva, Elena;Gershengorn, Marvin C.
内容：Graves病（GD）是由甲状腺刺激抗体（TSAb）激活TSH受体（TSHR）对甲状腺细胞的持续、不受调节的刺激引起的。我们之前报道了第一个人TSHR的小分子拮抗剂，并表明它可以抑制四名GD患者血清刺激的受体信号传导。目的：我们的目标是开发一种更好的TSHR拮抗剂，并使用它来确定抑制TSHR的TSAb激活是否是一种普遍现象。设计：我们的目的是化学修饰以前报道的小分子TSHR配体，以开发更好的拮抗剂，并确定它是否抑制TSHR信号转导30 GD血清。在两个体外系统中测量TSHR信号传导：稳定过表达人TSHR的模型HEK-EM 293细胞和人甲状腺细胞的原代培养物。TSHR信号测量cAMP的生产和甲状腺过氧化物酶mRNA.Results的影响：我们测试了类似物的小分子TSHR反向激动剂，并选择了最好的NCGC 00229600作进一步研究。在模型系统中，NCGC 00229600抑制基础和TSH刺激的cAMP产生。NCGC 00229600对TSH信号传导的抑制是竞争性的，即使它不竞争TSH结合;也就是说，NCGC 00229600是一种变构反向激动剂。NCGC 00229600对所有30份供试GD血清的cAMP生成抑制率为39 +/- 2.6%。在原代培养的人甲状腺细胞中，NCGC 00229600可抑制TSH受体介导的基础和GD患者血清中甲状腺过氧化物酶mRNA水平的上调，抑制率为65 ± 2.0%。结论：NCGC 00229600是一种小分子TSH受体反向激动剂，可拮抗TSAbs对GD患者血清中TSH受体的激活。（临床内分泌代谢杂志96：548-554，2011）
Context: Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor (TSHR). We previously reported the first small-molecule antagonist of human TSHR and showed that it inhibited receptor signaling stimulated by sera from four patients with GD.Objective: Our objective was to develop a better TSHR antagonist and use it to determine whether inhibition of TSAb activation of TSHR is a general phenomenon.Design: We aimed to chemically modify a previously reported small-molecule TSHR ligand to develop a better antagonist and determine whether it inhibits TSHR signaling by 30 GD sera. TSHR signaling was measured in two in vitro systems: model HEK-EM293 cells stably overexpressing human TSHRs and primary cultures of human thyrocytes. TSHR signaling was measured as cAMP production and by effects on thyroid peroxidase mRNA.Results: We tested analogs of a previously reported small-molecule TSHR inverse agonist and selected the best NCGC00229600 for further study. In the model system, NCGC00229600 inhibited basal and TSH-stimulated cAMP production. NCGC00229600 inhibition of TSH signaling was competitive even though it did not compete for TSH binding; that is, NCGC00229600 is an allosteric inverse agonist. NCGC00229600 inhibited cAMP production by 39 +/- 2.6% by all 30 GD sera tested. In primary cultures of human thyrocytes, NCGC00229600 inhibited TSHR-mediated basal and GD sera up-regulation of thyroperoxidase mRNA levels by 65 +/- 2.0%.Conclusion: NCGC00229600, a small-molecule allosteric inverse agonist of TSHR, is a general antagonist of TSH receptor activation by TSAbs in GD patient sera. (J Clin Endocrinol Metab 96: 548-554, 2011)