Intervention Strategies into Glycoprotein Hormone Receptors for Modulating (Mal–)function, with Special Emphasis on the TSH Receptor

Abstract

The thyrotropin receptor (TSHR), the lutropin- (LHR), and the follicotropin receptor (FSHR) belong to glycoprotein hormone receptors (GPHR), a subgroup of the class A G-protein coupled receptors. In this review, the unique features of GPHR have been taken into account for their pharmacological interventions: i) The respective hormone and stimulating or blocking antibodies are binding on the large ectodomain that is ii) via a hinge region, containing iii) an internal tethered agonist linked to the transmembrane domain. iv) Multimerization and mechanisms for negative or positive cooperativity of GPHR upon ligand binding and v) dimer- and oligomeric arrangements enabling trans-activation on GPHR signaling are considered. Available knowledge concerning the modulation of the GPHR (mal)-function and associated structural aspects by diverse entities such as antibodies, chaperones, peptides, small molecule agonists, inverse agonists, and antagonists is summarized. The TSHR is important with respect to autoimmune [Graves’ disease (GD), Graves’ orbitopathy (GO)] or non-autoimmune thyroid dysfunctions and cancer-development. To date there is neither an agonist nor antagonist modulator of pathogenic such as TSHR signaling in the clinics. However, several different ligands monoclonal stimulating and inhibiting antibodies and small molecule drug-like ligands have been reported in the last decade. In special focus are the most recent findings regarding the development and use of small molecule TSHR ligands. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts towards understanding the interplay of TSHR multimers, especially their interaction with drug-like ligands. Important in this context is the biased ligand development.

Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

“…CH and the internal agonist sequences are both embedded in between the ECLs of the seven TMH [reviewed in and Krause and Marcinkowski (2018)]. According to our own and other molecular models of TSHR (Kleinau and Vassart, 2017), CH interacts with ECL1, as is also supported by the strong CAM of S281Q (located at CH) and I486F (located at ECL1) (Fig.…”

“…Antithyroid drugs available on the market inhibit thyroid hormone synthesis in the thyroid gland but do not act directly on the TSHR and are therefore less effective in the treatment of GO (Sato et al, 2015). Small molecules acting directly on the TSHR are thought to interact allosterically in the transmembrane domain (TMD) as positive and negative allosteric modulators [(PAM, NAM), reviewed in Krause and Marcinkowski (2018)].…”

Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

“…An important advantage of these small organic molecule TSHR antagonists is their oral availability that would allow easier administration outside the clinic compared to antibodies that must be administered parenterally. Small molecule TSHR antagonists have been extensively reviewed recently [39], and therefore, we will focus on selected compounds. Latif et al [37] developed an indole-thiazole derivative named VA-K-14.…”

Hormone and Metabolic Research: 50 Years of Research

“…Most recently, we also focused on thyroid diseases, e. g. autoimmune thyroid disease; here another three special issues were published highlighting the genetic cause as well as the immunological background, diagnostic procedures and therapeutic options in Graves' disease and autoimmune thyroiditis, including a most recent special issue [16][17][18][19][20][21][22][23][24].…”