Allosteric Regulators of the Thyroid-Stimulating Hormone Receptor – New Horizons in the Pharmacology of Thyroid Pathology

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The thyroid stimulating hormone receptor (TSHR) expressed in the thyroid gland is a key component of the TSH-regulated signaling system responsible for the synthesis of thyroid hormones and the growth and proliferation of thyroid cells. The TSH receptor is also present in some non-thyroid tissues (bone tissue, orbital fibroblasts, etc.), controlling their physiological functions. It has a large ectodomain containing a high-affinity orthosteric site that binds TSH and autoantibodies to TSHR, as well as a transmembrane domain containing a significant number of allosteric sites with different localizations. Activation of TSHR by the hormone leads to the launch of a large number of signaling cascades mediated through various types of G proteins and β-arrestins. The selectivity and efficiency of activation of these cascades are largely determined by allosteric mechanisms, which include the formation of TSHR complexes, the effect on TSH signaling of the “internal” agonist localized at the C-terminus of the hinge loop of the TSHR ectodomain, and the N-glycosylation status of TSH. Changes in TSHR activity are the causes of a large number of thyroid diseases and other pathologies, but at present TSHR regulators are practically not used in medicine. Other therapy is not directly targeted at TSHR, which is associated with many of their side effects. Since the use of ligands of the TSHR orthosteric site carries significant risks, the attention of researchers is attracted by ligands of its allosteric sites, including those localized in the transmembrane channel. They have a wide profile of pharmacological activity, including regulators with their own activity (direct and inverse agonists, and neutral antagonists), modulators of TSH effects (PAM, NAM, SAM, and BAM) and regulators with combined activity (ago-PAM, ago-NAM). Allosteric ligands are endowed with moderate activity, without causing hyperactivation or complete blockade of TSHR, in many cases demonstrate selectivity for certain signaling cascades, and retain activity when administered orally. Thus, they can be used to treat various thyroid diseases, including Graves' disease, Hashimoto's thyroiditis, primary hypothyroidism, adenomas and thyroid cancer, as well as Graves' ophthalmopathy and diseases of the musculoskeletal system. The review systematizes and analyzes data on low-molecular allosteric regulators of TSHR developed by us and other authors, and assesses the prospects for their use in the clinic.

作者简介

A. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: alex_shpakov@list.ru
St. Petersburg, Russia

K. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

St. Petersburg, Russia

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