In mammals, parathyroid hormone (PTH) [1], an 84 amino acid hormone, plays a vital role in regulating the concentrations of ionized calcium and phosphate in the blood and extracellular fluids. It has been shown that the first 34 amino acid fragment of PTH is sufficient to bind to and activate the PTH type I receptor (PTH1R), a heptahelical transmembrane G protein-coupled receptor. The molecular mechanisms by which PTH(l-34) binds to and activates the PTH1R have been extensively investigated [2]. The study of miniaturized PTH agonist and antagonist analogues has been the subject of extensive research [3], for the development of safer and non-parenteral bone anabolic drugs. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH1R showed that certain modifications can increase signalling potency in peptides as short as 11 amino acids. To understand the role of the side-chains of all amino acid residues of the most active analogue of PTH(1-11), H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2 (RP), we carried out a D-amino acid scan in which every L-AA was substituted with the corresponding D-AA, obtaining a library of PTH(1-11) analogues which were tested for agonistic activity (Tab.1).
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