Discovery of a Long-Acting Parathyroid Hormone 1–34 Analogue to Treat Hypoparathyroidism

Abstract

Hypoparathyroidism (HP) is a rare disease with clinical manifestations of hypocalcemia and hyperphosphatemia, resulting from deficient or absent parathyroid hormone (PTH) secretion. Conventional treatment for patients with HP involves extensive calcium and vitamin D supplementation. In 2015, PTH1–84 was approved by the United States Food and Drug Administration as an adjunct for HP patients who cannot be well-controlled on conventional treatment. However, PTH1–84 therapy requires a daily injection, leading to poor patient compliance. The purpose of this study was to develop a long-acting PTH1–34 analogue by increasing its affinity to albumin. Three PTH1–34 variants were generated by substituting two of the three lysine (Lys) residues with arginine, reserving a single Lys as the modification site in each sequence. A series of side chains, containing fatty acid, deoxycholic acid, or biotin groups, were synthesized to modify these PTH1–34 variants by using a solid–liquid phase synthesis approach. In vitro bioactivity and albumin affinity tests were used to screen these new PTH1–34 analogues. Finally, Lys27-AAPC was selected from 69 synthesized analogues as a candidate therapeutic compound because it retained potency and exhibited a high albumin-binding capacity. In pharmacodynamic experiments, Lys27-AAPC demonstrated enhanced and prolonged efficacy in serum calcium elevating relative to PTH1–84. Moreover, a lyophilized powder for injection containing Lys27-AAPC was developed for further testing and represented a potential long-acting HP treatment.

Endocrine manifestations in adults with 22q11.2 deletion syndrome: a retrospective single-center cohort study

“…Recombinant human PTH 1-84 has been FDA- and EMA-approved for use in patients with hypoparathyroidism not well controlled by conventional therapy, but this treatment is unavailable in many countries (such as Belgium) [ 12 ]. New drugs, such as long-acting PTH analogs, are emerging [ 13 ]. Over time, both hypoparathyroidism and its treatment may result in ectopic soft tissue calcifications in the brain (mainly in the basal ganglia), the eyes (cataracts) and the kidneys (stones and nephrocalcinosis), which has been attributed to an elevated calcium-phosphate product and chronic hypercalciuria, in particular under treatment with vitamin D analogs.…”