ROLE OF THE GUANIDINE GROUP IN POSITION 11 OF PTH(1-11) ANALOGUES

The N-terminal 1-34 fragment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses characteristic of the native intact PTH. Recent studies have demonstrated that helicity-enhancing substitutions yielded potent analogues of PTH(1-11) and PTH(1-14). The role of alpha-helicity on biological potency is well known. In the context of searching the pharmacological properties of PTH(1-11) analogues, we studied the role of a positive charge at the C-terminal position, which was identified to play an essential role in bioactivity and binding. A series of modified peptide analogues of PTH(1-11) was synthesized and characterized. As a reference, we synthesized an analogue containing Lys in position 11. This analogue exhibited an activity similar to that of [Ala1,3, Gln10, Har11]PTH(1-11)NH2, reference peptide. The peptide series was synthesised by SPPS employing Fmoc protected amino acids and a small library of Fmoc-protected glutamic acid amides of variable chain length previously prepared in solution. A circular dichroism study of the synthesized peptides was performed to compare their conformation with biological activity. We found a reduced activity for modified analogues which could be justified by the role of the C-terminal amide group. New syntheses of analogues containing mimetics are underway to establish the correlation between the guanidine function and bio-activity of PTH(1-11) analogues.