Bioactive N-terminal Undecapeptides Derived from Parathyroid Hormone. The Role of alpha-Helicity

Parathyroid hormone (PTH) is an 84 amino acids peptide responsible for the regulation of calcium levels in blood and kidney [1]. The N-terminal (1-34) sequence is a fully active form of this hormone. In vivo it can reproduce all biological responses characteristic to the native intact PTH. Enhancement of a-helicity in the PTH(1-14) and PTH(1-11) sequences yielded potent analogues of PTH(1-14)NH2 [2]. This report presents our efforts to stabilize the structure and to increase the helical content of the short hPTH(1-11) sequence. We synthesised and characterized the following hPTH(1-11) analogues substituted in positions 1 and 3 by the following tetra-substituted amino acid residues: Aib, 1-aminocyclopentane-1-carboxylic acid (Ac5c) and 1-aminocyclohexane-1-carboxylic acid (Ac6c). The most potent analogue exhibits biological activity 3500-fold higher than that of the native sequence PTH(1-11) and only 15-fold weaker that that of the full native sequence hPTH-(1-34). In the NOESY spectra, a number of aH(i)-HN(i+3), aH(i)-bH(i+3) connectivities and also one aH(i)-HN(i+4) connectivity typical of the a-helix were observed in the segment 2-10. These results stress the importance of the presence of a helical segment at the N-terminus of PTH (1-34) analogues at the effect of biological activity.