Structure and Activities of Constrained Analogues of Human Parathyroid Hormone and Parathyroid Hormone-Related Peptide: Implications for Receptor-Activating Conformations of the Hormones

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Abstract
Parathyroid hormone (PTH) has a helix−bend−helix structure in solution. Part of the C-terminal helix, residues 21−31, is amphiphilic and forms a critical receptor-binding region. Stabilization of this α-helix by lactam formation between residues spaced i, i + 4 on the polar face was previously reported to increase adenylyl cyclase-stimulating (AC) activity if between residues 22 and 26 but to diminish it if between residues 26 and 30 [Barbier et al. (1997) J. Med. Chem. 40, 1373−1380]. This work reports the effects of other cyclizations on the polar face, differing in ring size or position, on α-helix conformation, as measured by circular dichroism, and on AC-stimulating activity. All analogues cyclized between residues 22 and 26 had at least a 1.5-fold increase in activity, suggesting an α-helical structure between about residues 21 and 26. Cyclization between residues 25 and 29 or residues 26 and 30 diminished activity by 20−30%, despite stabilizing α-helix, suggesting that residues 25−31 bind to the receptor in a helical, but not classical α-helical, conformation. Analogues cyclized between residues 13 and 17 had slightly increased activity. A bicyclic analogue, with lactams between residues 13 and 17 and residues 22 and 26, had about the same activity as that cyclized only between 22 and 26. Parathyroid hormone-related peptide (PTHrP) may bind in a manner similar to the common receptor, but hydrophobic moment calculations suggest that it must bind as a tighter helix in order to optimally present its hydrophobic residues to the receptor. Both PTHrP analogues cyclized between either residues 22 and 26 or residues 26 and 30 had more stable α-helices but reduced AC activities, consistent with this hypothesis.

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