Function-structure relationship of PHT(1-11) analogues

Parathyroid hormone (PTH) is an 84 amino acid peptide hormone produced in the parathyroid glands. It acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. It has been shown that the 1-34 N-terminal fragment of PTH is sufficient to bind and activate the PTH type I receptor (PTH1R). The study of reduced-size PTH agonist and antagonist analogues has been the subject of extensive research for the development of bone anabolic drugs. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH1R showed that some modifications can increase signalling potency in peptides as short as 11 amino acid residues (e.g. S3→A3, N10→Q10, L11→R11). This work of PhD thesis represents our effort to investigate the role of side chains and structural characteristics of N-terminal domain of PTH(1-11). We applied the hierarchical approach and some peptidomimetics concepts to synthesize specific libraries of peptide to obtain information about hormone/receptor interaction. With these information, we have been able to project a first example of peptidomimetic of PTH. The strategical role of Val2 in the interaction with the PTH1R receptor was demonstrated and confirmed. We have observed that guanidine group in C-terminus has a specific role in the binding to the receptor for the shortest PTH(1-11) fragment. We have shown that substitutions with alpha-MeNle at positions 8 can increase helix stability which can be also stabilized and promoted through a bridge between 6 and 10 positions. We synthesized a group of active analogues which are characterized by a stable alpha-helix in all peptide sequences and have the correct orientation of essential esidues 2, 5, 8 and 11