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[摘要]：The N-terminal region of the parathyroid hormone (PTH) is sufficient to activate the G-protein-coupled PTH receptor 1 (PTH 1). The shortest PTH analogue displaying nanomolar potency is the undecapeptide H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2 that contains two helix-stabilizing residues (Aib(1.3)). To increase the helical character and proteolytic stability of this linear peptide. We replaced Gln(6,10) with (a) Lys(6) and Glum to introduce a lactam bridge and (b)Ser(6.10) to form a Wester bridge upon cross-linking with adipic acid. These cyclopeptides were, respectively, 468-fold less and 12-fold more potent agonists than the linear analogue. Despite their different potencies, all three analogues adopted similar alpha-helix structures, as shown h NMR and molecular dynamics studies, However, the diester bridge could better mimic the orientation and chemical properties of the side chains of Gln(6) and Gln(10) in the linear PTH analogue than the lactam moiety. This is apparently important for efficient receptor activation and provides further insights into the receptor-bound ligand conformation. |
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