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Structure-function relationship studies of PTH(1-11) analogues containing sterically hindered dipeptide mimetics
- Source :
- Journal of peptide science : an official publication of the European Peptide Society. 13(8)
- Publication Year :
- 2007
-
Abstract
- The N-terminal 1–34 fragment of parathyroid hormone (PTH) is fully active in vitro and in vivo and reproduces all biological responses characteristic of the native intact PTH. In order to develop safer and non-parenteral PTH-like bone anabolic agents, we have studied the effect of introducing conformationally constrained dipeptide mimetics into the N-terminal portion of PTH in an effort to generate miniaturized PTH-mimetics. To this end, we have synthesized and conformationally and biologically characterized PTH(1–11) analogues containing 3R-carboxy-6S-amino-7,5-bicyclic thiazolidinlactam (7,5-bTL), a rigidified dipeptide mimetic unit. The wild type sequence of PTH(1–11) is H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-NH2. The following pseudo-undecapeptides were prepared: [Ala1, 7,5-bTL3, 4, Nle8, Arg11]hPTH(1–11)NH2 (I); [Ala1, 7,5-bTL6, 7, Nle8, Arg11]hPTH(1–11)NH2 (II); [Ala1, Nle8, 7,5-bTL9, 10, Arg11]hPTH(1–11)NH2 (III). In aqueous solution containing 20% TFE, only analogue I exhibited the typical CD pattern of the α-helical conformation. NMR experiments and molecular dynamics calculations located the α-helical stretch in the sequence Ile5-His9. The dipeptide mimetic unit 7,5-bTL induces a type III β-turn, occupying the positions i − 1 and i of the turn. Analogue II exhibited an equilibrium between a type I β-turn and an α-helix, and analogue III did not show any ordered structure. Biological tests revealed poor activity for all analogues (EC50 > 0.1 mM). Apparently, the relative side-chain orientation of Val2, Ile5 and Met8 can be critical for effective analogue-receptor interaction. Considering helicity as an essential property to obtain active PTH agonists, one must decorate the correctly positioned dipeptide mimetic azabicycloalkane scaffold with substitutions corresponding to the displaced amino acids. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
- Subjects :
- Steric effects
Molecular model
Stereochemistry
Parathyroid hormone
Peptide
Biochemistry
Protein Structure, Secondary
Cell Line
Turn (biochemistry)
chemistry.chemical_compound
Structure-Activity Relationship
Isomerism
Structural Biology
Drug Discovery
Humans
Molecular Biology
Pharmacology
chemistry.chemical_classification
Dipeptide
Organic Chemistry
Wild type
General Medicine
Dipeptides
Combinatorial chemistry
Peptide Fragments
Amino acid
chemistry
Parathyroid Hormone
Molecular Medicine
Subjects
Details
- ISSN :
- 10752617
- Volume :
- 13
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Journal of peptide science : an official publication of the European Peptide Society
- Accession number :
- edsair.doi.dedup.....b45d132b47ac54457c34201c8614bc4c