Synthesis and structural studies of new analogues of PTH(1-11) containing Cα-tetra-substituted amino acids in position 8.
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. Recently, analogues of PTH(1-11) fragments with helicity-enhancing substitutions have been demonstrated to yield potent analogues of PTH(1-34). The work describes the synthesis, biological activity and structure of analogues of the best modified PTH sequence H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2 (I). In particular, the effect of the Ala/Aib substitution at positions 1 and 3 as well as of the replacement of Nle in position 8 with D-Nle, L-(αMe)-Nle and D-(αMe)-Nle was studied. The resulting peptides were characterized structurally by CD spectroscopy, solution NMR and MD, and in vitro for activity with respect to the cognate receptor, parathyroid hormone receptor.
Caporale
Andrea
A
Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131, Padova, Italy. caporaleandrea74@gmail.com
Sturlese
Mattia
M
Schievano
Elisabetta
E
Mammi
Stefano
S
Peggion
Evaristo
E
D000596:Amino Acids / Q000737:chemistry*; D002478:Cells, Cultured; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010281:Parathyroid Hormone / Q000138:chemical synthesis* / Q000737:chemistry*; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
D000596:Amino Acids; D010281:Parathyroid Hormone; D010446:Peptide Fragments; C454802:parathyroid hormone (1-11)