Structure–function relationship studies of PTH(1–11) analogues containing D-amino acids

Caporale, Andrea; Biondi, Barbara; Schievano, Elisabetta; Wittelsberger, Angela; Mammi, Stefano; Peggion, Evaristo

doi:10.1016/j.ejphar.2009.03.040

Cited by 14 publications

(26 citation statements)

References 44 publications

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“…In contrast, the agonist profile of MPTH(1-28) is similar to that of PTH(1-34), suggesting that N-terminal AA substitutions increasing a-helicity of the N-terminal domain (Okazaki et al, 2008) help maintain agonist activity of PTH(1-28) analogs. However, introduction of the same AA substitutions into more extensive C-terminal truncated peptides helps predominately to maintain agonist activity to stimulate G s -signaling, as reported by others (Shimizu et al, 2001(Shimizu et al, , 2004Caporale et al, 2009Caporale et al, , 2010Neerup et al, 2011). The structural basis for the greater capacity of PTH(1-28), [Gly 1 ,Arg 19 ]PTH(1-28), ZP2307, and MPTH(1-14) to stimulate receptor internalization is unclear but may be a result of C-terminal AAs present in PTH(1-31) providing a restraint on receptor internalization.…”

Section: Discussionmentioning

confidence: 89%

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Cupp¹,

Nayak²,

Adem³

et al. 2013

J Pharmacol Exp Ther

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Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), acting through the osteoblast PTH1 receptor (PTH1R), play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation, whereas continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including G s /cAMP/protein kinase A, G q /calcium/protein kinase C, b-arrestin recruitment, and extracellular signal-related kinase (ERK)1/2 phosphorylation, as well as receptor internalization, but their role in promoting anabolic and catabolic actions of PTH(1-34) are unclear. In the present investigation, a collection of PTH(1-34) and PTHrP(1-34) peptide analogs were evaluated in orthogonal human PTH1R (hPTH1R) functional assays capturing G s -and G q -signaling, b-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization to further define the patterns of PTH1R signaling that they stimulate and further establish peptide domains contributing to agonist activity. Results indicate that both Nand C-terminal domains of PTH and PTHrP are critical for activation of signaling pathways. However, modifications of both regions lead to more substantial decreases in agonist potency and efficacy to stimulate G q -signaling, b-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization than to stimulate G s -signaling. The substantial contribution of the peptide C-terminal domain in activation of hPTH1R signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain. Several PTH and PTHrP peptides evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts. With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 89%

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Cupp¹,

Nayak²,

Adem³

et al. 2013

J Pharmacol Exp Ther

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“…4). The N-terminal modifications, which typically include conformationally constraining amino acid analogs, such as a-amino isobutyric acid substituted at positions 1 and/or 3, also conferred detectable cAMP-signaling potency to the otherwise inactive PTH(1-11) peptide (Shimizu et al, 2001a(Shimizu et al, ,b, 2004, along with at least some a-helicity (Barazza et al, 2005;Fiori et al, 2007;Caporale et al, 2009aCaporale et al, ,b, 2010Cupp et al, 2013b). It thus may be that for the native ligand, the N-terminal domain becomes structurally more organized as an a-helix upon binding to the receptor (Shimizu et al, 2001b(Shimizu et al, , 2004, as has been suggested for other peptide ligands that bind to a family B GPCR (Parthier et al, 2009).…”

Section: B Parathyroid Hormone-related Proteinmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

2015

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“…For this purpose, we decided to use both active and completely inactive analogues containing residues mimicking Val in position 2. The sensitive role of Val 2 has been demonstrated by the potency decrease due to the simple modification of the side chain orientation (Caporale et al 2009a). In this work, a CD and 2-D NMR conformational analysis was performed on the most relevant analogues synthesized.…”

Section: Abbreviationsmentioning

confidence: 99%

“…Some modifications recently introduced in position 2, such as a D-Val residue (Caporale et al 2009a), reduce or annihilate the activity of the most active PTH (1-11) analogue, H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-GlnHar-NH 2 (I). We interpreted this behaviour as the consequence of an unsuitable orientation of the Val side chain, rather than of an overall 3-D structural alteration caused by the presence of non-proteinogenic amino acids.…”

Section: Abbreviationsmentioning

confidence: 99%

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Design, conformational studies and analysis of structure–function relationships of PTH (1–11) analogues: the essential role of Val in position 2

et al. 2011

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The N-terminal 1-34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it elicits all the biological responses characteristic of the native intact PTH. Recent studies reported potent helical analogues of the PTH (1-11) with helicity-enhancing substitutions. This work describes the synthesis, biological activity, and conformational studies of analogues obtained from the most active non-natural PTH (1-11) peptide H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2; specifically, the replacement of Val in position 2 with D-Val, L-(αMe)-Val and N-isopropyl-Gly was studied. The synthesized analogues were characterized functionally by in-cell assays and their structures were determined by CD and NMR spectroscopy. To clarify the relationship between the structure and activity, the structural data were used to generate a pharmacophoric model, obtained overlapping all the analogues. This model underlines the fundamental functional role of the side chain of Val2 and, at the same time, reveals that the introduction of conformationally constrained Cα-tetrasubstituted α-amino acids in the peptides increases their helical content, but does not necessarily ensure significant biological activity.

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Structure–function relationship studies of PTH(1–11) analogues containing D-amino acids

Cited by 14 publications

References 44 publications

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

Design, conformational studies and analysis of structure–function relationships of PTH (1–11) analogues: the essential role of Val in position 2

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