Inactivation of Parathyroid Hormone: Perspectives of Drug Discovery to Combating Hyperparathyroidism

Abstract

: Hormonal coordination is tightly regulated within the human body and thus regulates human physiology. The parathyroid hormone (PTH), a member of the endocrine system, regulates the calcium and phosphate level within the human body. Under non-physiological conditions, PTH levels get upregulated (hyperparathyroidism) or downregulated (hypoparathyroidism) due to external or internal factors. In the case of hyperparathyroidism, elevated PTH stimulates cellular receptors present in the bones, kidneys, and intestines to increase the blood calcium level, leading to calcium deposition. This eventually causes various symptoms including kidney stones. Currently, there is no known medication that directly targets PTH in order to suppress its function. Therefore, it is of great interest to find novel small molecules or any other means that can modulate PTH function. The molecular signaling of PTH starts by binding of its N-terminus to the G-protein coupled PTH1/2 receptor. Therefore, any intervention that affects the N-terminus of PTH could be a lead candidate for treating hyperparathyroidism. As a proof-of-concept, there are various possibilities to inhibit molecular PTH function by (i) a small molecule, (ii) N-terminal PTH phosphorylation, (iii) fibril formation and (iv) residue-specific mutations. These modifications put PTH into an inactive state, which will be discussed in detail in this review article. We anticipate that exploring small molecules or other means that affect the N-terminus of PTH could be lead candidates in combating hyperparathyroidism.

The pro‐sequence of parathyroid hormone prevents premature amyloid fibril formation

“…For proPTH the competition with PTH represents one perspective for drug development to treat hyperparathyroidism. As PTH 1–84 and PTH 1–34 and their formulations are already approved drugs for the treatment of osteoporosis [4] we anticipate that competing proPTH might serve as a compound for a proper blood level adjustment during hormone therapy. Functional amyloids of hormones had been put into perspective as a formulation of long‐acting drugs [42].…”

“…The induced cascade via heterotrimeric G proteins converts the signal into a modulated flow of second messengers including cyclic AMP (cAMP), inositol triphosphate, diacylglycerol, or cGMP [2]. As these second messengers modulate skeletal, endocrine, cardiovascular, or nervous cell function [3], PTH 1–84 and PTH 1–34 are approved drugs against osteoporosis [4]. In PTH‐secreting parathyroid tissue derived from both normal and overactive parathyroid glands, early studies identified intrafollicular amyloids [5].…”