Cyclic parathyroid hormone-related protein antagonists: lysine 13 to aspartic acid 17 [i to (i + 4)] side chain to side chain lactamization

Abstract

Cyclization of parathyroid hormone related protein (7-34)amide [PTHrP(7-34)NH2] via covalent bond formation between the epsilon-amino of Lys13 and the beta-carboxyl of Asp17 yielded a 20-membered ring lactam. This analogue, [Lys13,Asp17]PTHrP(7-34)NH2, was 5-10-fold more potent than the linear parent peptide (Kb = 15 and 18 nM in PTH receptor binding assays, and Ki = 130 and 17 nM in PTH-stimulated adenylate cyclase assays in bovine renal cortical membrane and in human bone derived B10 cells, respectively). In contrast, a linear analogue in which charges in positions 13 and 17 were eliminated and other stereoisomers of the above-mentioned lactam in which either Lys13 and/or Asp17 were replaced by the corresponding D-amino acids were much less potent with regard to antagonist bioactivity than the parent peptide. The rationale for the design of the lactam as well as the conformational implications for the PTHrP sequence in light of reported models suggested for the 1-34 peptide are described. The potential use of conformationally constrained analogues for elucidating the "bioactive conformation" of antagonists and for the design of substantially simplified molecular structures for antagonists is discussed.

CuI‐Catalyzed Azide–Alkyne Intramolecular i‐to‐(i+4) Side‐Chain‐to‐Side‐Chain Cyclization Promotes the Formation of Helix‐Like Secondary Structures

“…derived from parathyroid hormone-related peptide (PTHrP) [1] (Scheme 1, III) and compared its conformational preferences with the cor- [14,15] share the same spatial orientation of the side-chains of Ser, Gln, and Ile located at the i+1 to i+3 positions of the ring-forming sequences. [13] Herein we report on the synthesis and a comprehensive conformational analysis of a series of i-to-(i+4) side-chainto-side-chain 1,4-disubstituted 1,2,3-triazolyl-bridged cyclononapeptides (Scheme 1, I-VIII, except III that was reported previously) [1] derived from the model peptide N α -Ac-PTHrP(11-19)NH 2 .…”

α-Helix nucleation by a calcium-binding peptide loop

“…Several such systems have been devised and used successfully to nucleate the helix by covalent (5)(6)(7)(8)(9)(10)(11)(12) or metal-induced (13,14) side chain-side chain bridges. All of them reduce the entropy change related to the helix nucleation and, consequently, lead to a large increase of parameter, but none of them provides an ideal nucleation site composed of a few residues fixed in the rigid ␣-helical structure.…”

How To Stabilize or Breakβ-Peptidic Helices by Disulfide Bridges: Synthesis and CD Investigation ofβ-Peptides with Cysteine and Homocysteine Side Chains

“…CD Spectroscopy. ± As concluded from numerous CD measurements and corresponding NMR structural investigations of b-peptides [1] [2] [8] [9], the CD pattern of a trough at ca. 216 and a peak at ca.…”