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'

• Applicant: Dr. Gerd Krause
• Subject Area: Endocrinology, Diabetology, Metabolism ; Ophthalmology
• Term: from 2009 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 131071061

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.

• DFG Programme: Research Grants