Design and Applications of Parathyroid Hormone Analogues

Morley, Paul; Jf, Whitfield; Ge, Willick

doi:10.2174/092986730611220401164817

Cited by 25 publications

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“…Our studies here revealed that the same linear hPTH(1−31)NH 2 peptide has the best defined solution structure (Figure ) among all bioactive PTH fragments. It has been shown recently that the anabolic activites of hPTH(1−31)NH 2 can be further enhanced by replacing Lys27 with Leu and by cyclization of the side chains of Glu22 and Lys26 through lactam formation ( , ). The folded structure of hPTH(1−31)NH 2 indeed places the side chains of residues Glu22 and Lys26 in spatial proximity (Figures and ).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it will be extremely important to determine the biological activities of a PTH peptide constrained into the “folded” and V-shape conformation to assess whether the solution structure determined here for hPTH(1−31)NH 2 (Figure ) represents at least one of the bioactive conformations for PTH peptides. This is especially true if one considers the fact that the parathyroid hormone has pleiotropic activities ( − ), which may be expressed through the binding to different receptor subtypes of which two have been identified to date (). Better understanding of the structure−activity relationship of the PTH molecules will also come from the characterization of the solution conformations of selectively cyclized PTH analogues and ultimately the three-dimensional structures of PTH peptides in complex with well-defined receptor targets.…”

Section: Discussionmentioning

confidence: 99%

“…PTH functions principally through its actions on the seven transmembrane G-protein-linked receptors in kidney, bone, and intestinal cells. The PTH-receptor interactions activate two distinct signaling pathways, one involving the adenylyl cyclase (AC) and AC-associated protein kinase A and another involving the phospholipase Cβ and the associated protein kinase C (PKC) (1)(2)(3). Virtually all the functions of human PTH (hPTH) are encoded within the N-terminal 34 amino acid residues of the 84-residue full-length protein, as the 1-34 peptide fragment, or hPTH , is fully active (4) and displays both AC stimulation and PKC activities (5).…”

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confidence: 99%

“…In addition, hPTH-(1-31)NH 2 was found to have comparable AC-stimulating activity to hPTH , but it did not cause hypercalcemia, thus appearing not to cause rapid bone resorption in humans (14) as can result from hPTH treatment. As such, selectively osteogenic analogues of human PTH may represent a new generation of therapeutics for the treatment of osteoporosis (2,15).…”

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Solution Structure of the Osteogenic 1−31 Fragment of the Human Parathyroid Hormone

Chen

Barbier

et al. 2000

Biochemistry

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The solution conformations of a selectively osteogenic 1-31 fragment of the human parathyroid hormone (hPTH), hPTH(1-31)NH(2), have been characterized by use of very high field NMR spectroscopy at 800 MHz. The combination of the CalphaH proton and (13)Calpha chemical shifts, (3)J(NH)(alpha) coupling constants, NH proton temperature coefficients, and backbone NOEs reveals that the hPTH(1-31)NH(2) peptide has well-formed helical structures localized in two distinct segments of the polypeptide backbone. There are also many characteristic NOEs defining specific side-chain/backbone and side-chain/side-chain contacts within both helical structures. The solution structure of hPTH(1-31)NH(2) contains a short N-terminal helical segment for residues 3-11, including the helix capping residues 3 and 11 and a long C-terminal helix for residues 16-30. The two helical structures are reinforced by well-defined capping motifs and side-chain packing interactions within and at both ends of these helices. On one face of the C-terminal helix, there are side-chain pairs of Glu22-Arg25, Glu22-Lys26, and Arg25-Gln29 that can form ion-pair and/or hydrogen bonding interactions. On the opposite face of this helix, there are characteristic hydrophobic interactions involving the aromatic side chain of Trp23 packing against the aliphatic side chains of Leu15, Leu24, Lys27, and Leu28. There is also a linear array of hydrophobic residues from Val2, to Leu7, to Leu11 and continuing on to residues His14 and Leu15 in the hinge region and to Trp23 in the C-terminal helix. Capping and hydrophobic interactions at the end of the N-terminal and at the beginning of the C-terminal helix appear to consolidate the helical structures into a V-shaped overall conformation for at least the folded population of the hPTH(1-31)NH(2) peptide. Stabilization of well-folded conformations in this linear 1-31 peptide fragment and possibly other analogues of human PTH may have a significant impact on the biological activities of the PTH peptides in general and specifically for the osteogenic/anabolic activities of bone-building PTH analogues.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Solution Structure of the Osteogenic 1−31 Fragment of the Human Parathyroid Hormone

Chen

Barbier

et al. 2000

Biochemistry

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“…Accumulated data show that the PTH C-terminal helix binds with its hydrophobic face to the long N-terminal extracellular sequence of its receptor and that residues Arg-20, Trp-23, Leu-24, and Leu-28 are critical for the binding (4,48,49). Furthermore, in the context of hPTH(1-31)-NH 2 , the backbone nitrogen of Leu-28, but not Gln-29, is critical.…”

Section: Discussionmentioning

confidence: 99%

C-Terminal Analogues of Parathyroid Hormone: Effect of C-Terminus Function on Helical Structure, Stability, and Bioactivity

et al. 2006

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We have studied the effects of C-terminal group modifications (amide, methylamide, dimethylamide, aldehyde, and alcohol) on the conformation, adenylyl cyclase stimulation (AC), or binding of parathyroid hormone (hPTH) analogues, hPTH(1-28)NH(2) and hPTH(1-31)NH(2). hPTH(1-31)NH(2) has a C-terminal alpha-helix bounded by residues 17-29 [Chen, Z., et al. (2000) Biochemistry 39, 12766]. In both cases, relative to the natural analogue with a carboxyl C-terminus, the amide and methylamide had increased helix content whereas the dimethylamide forms had CD spectra more similar to the carboxyl one. Conformational effects were more pronounced with hPTH(1-28) than with hPTH(1-31), with increases in helix content of approximately 30% in contrast to 10%. Stabilization of the C-terminal helix of residues 1-28 seemed to correlate with an ability of the C-terminal function to H-bond appropriately. None of the analogues affected the AC stimulating activity significantly, but there was an up to 15-fold decrease in the level of apparent binding of the carboxyl hPTH(1-28) analogue compared to that of the methylamide and a 4-fold decrease in the level of binding of the aldehyde or dimethylamide. There was no significant change in binding activities for the 1-31 analogues. These observations are consistent with previous studies that imply the importance of a region of the hormone's C-terminal alpha-helix for tight binding to the receptor. They also show that modulation of helix stability does have an effect on the binding of the hormone, but only when the C-terminus is at the putative end of the helix. The similarity of AC stimulation even when binding changed 10-fold can be explained by assuming greater efficacy of the weaker binding PTH-receptor complexes in stimulating AC.

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Metabolic bone disease: Lessons from knockout mice

Karaplis

2000

Drug Dev. Res.

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Design and Applications of Parathyroid Hormone Analogues

Cited by 25 publications

References 0 publications

Solution Structure of the Osteogenic 1−31 Fragment of the Human Parathyroid Hormone

Solution Structure of the Osteogenic 1−31 Fragment of the Human Parathyroid Hormone

C-Terminal Analogues of Parathyroid Hormone: Effect of C-Terminus Function on Helical Structure, Stability, and Bioactivity

Metabolic bone disease: Lessons from knockout mice

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