New TSHR Antagonists as a potential approach to bridge the therapeutic gap of Graves' ophthalmopathy as follow up to' Modulators fort he Thyrotropin receptor: Molekular mechansims allosteric binding and mode of action of small molecules'

由自身抗体激活促甲状腺激素受体(TSHR)引起的Graves眼病(GO)是一种罕见的影响眼眶组织的疾病。这种炎症性自身免疫性疾病的严重病例的临床治疗仍然遇到了限制。GO在眼后成纤维细胞中启动，与TSHR在甲状腺中的信号通路不同。一种可能的直接靶向TSHR的方法是使用小分子(SM)拮抗剂来防止其病理性激活。我们以前的研究不仅积累了跨膜TSHR结合部位和SM形状之间的互补结构和功能信息，而且还发现了两个对TSHR表现出不同拮抗特征的分子作为进一步研究的起始支架。基于这些发现，新的提案将探索SM拮抗剂不同偏向的信号阻断的新想法，这可能解决TSHR的不同位置，对不同的信号通路产生偏向影响。其目的是描绘配体结合部位，物质修饰以增强亲和力和解决不同的途径，以及在更生理条件下测试GO患者眼眶成纤维细胞中的化合物及其对受体内化的影响。这些研究的结果将有助于我们从分子水平理解与自身抗体在GO时激活TSHR相关的疾病的发病机制。此外，对决定因素和分子机制的详细了解，将导致对不同信号通路的定向影响，这将为未来的药物干预奠定重要的基础研究，从长远来看，通过更有效和更定向的作用拮抗剂来弥合GO的治疗差距。

Graves' ophthalmopathy (GO) caused by autoantibodies activating the thyrotropin receptor (TSHR) is a rare disorder affecting the orbital tissue. Clinical treatment of severe cases of this inflammatory autoimmune disease still encounters its limits. GO initiates in retro-occular fibroblasts different signaling pathways compared to TSHR in the thyroid. One possible approach targeting the TSHR directly are small molecule (SM) antagonists to prevent its pathological activation. Our previous studies accumulated not only complementary structure-function information between a transmembrane TSHR binding site and shapes of SM, but identified also two molecules exhibiting different antagonistic profiles for TSHR as starting scaffolds for further studies. Based on these findings the new proposal will explore the novel idea of differently biased signaling blockage by SM antagonists that may address different locations of TSHR with biased impact on distinct signaling pathways. The aims are delineation of ligand binding sites, substance modifications to enhance the affinity and addressing distinct pathways as well as testing compounds in more physiological conditions at orbital fibroblasts of GO patients and the effects on receptor internalizations. The outcome of these studies will be relevant to our molecular understanding of the pathogenesis of diseases linked with pathological activation of TSHR by autoantibodies at GO. Moreover, detailed knowledge about determinants and molecular mechanisms, which lead to the directed impact on distinct signalling pathways will establish a substantial contribution of basic research for future pharmacological interventions to bridge the therapeutic gap of GO by means of more effective and more directed acting antagonists in the long term.