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'

摘要由自身抗体激活促甲状腺素受体（TSHR）引起的Graves眼病（GO）是一种影响眼眶组织的罕见疾病。临床治疗的严重情况下，这种炎症性自身免疫性疾病仍然遇到其局限性。与甲状腺中的TSHR相比，氧化石墨烯在眼后成纤维细胞中启动不同的信号通路。一种可能的方法是直接靶向TSHR的小分子（SM）拮抗剂来阻止其病理激活。我们之前的研究不仅积累了跨膜TSHR结合位点和SM形状之间的互补结构-功能信息，而且还鉴定了两种对TSHR具有不同拮抗特性的分子，作为进一步研究的起始支架。基于这些发现，新提案将探索SM拮抗剂不同偏倚信号阻断的新思路，这可能针对TSHR的不同位置，对不同的信号通路产生偏倚影响。目的是描述配体结合位点，物质修饰以增强亲和力，解决不同的途径，以及在氧化石墨烯患者的眼眶成纤维细胞中测试更多生理条件下的化合物，以及对受体内化的影响。这些研究的结果将与我们对与氧化石墨烯自身抗体病理激活TSHR相关的疾病发病机制的分子理解相关。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直接影响，为未来的药理干预奠定基础研究的重大贡献，从而通过长期更有效、更直接的拮抗剂来弥补氧化石墨烯的治疗空白。

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.