Title:Inactivation of Parathyroid Hormone: Perspectives of Drug Discovery to
Combating Hyperparathyroidism
Volume: 15
Author(s): Amit Kumar*Jochen Balbach*
Affiliation:
- Department of Life Sciences, Faculty of Natural Sciences, Imperial College of Science, Technology and Medicine London,
South Kensington, London SW7 2BUUK
- Institute of Physics, Biophysics, Martin–Luther–University Halle–Wittenberg,
Germany
- Institute of Physics, Biophysics, Martin–Luther–University Halle–Wittenberg,
Germany
- Institute of Technical Biochemistry e.V. and Centre for Structure und Dynamics of Proteins, Martin–
Luther–University Halle–Wittenberg, Germany
Keywords:
Hormone function, hyperparathyroidism treatment, PTH hormone, small molecules, protein phosphorylation, amyloid formation.
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 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 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.
