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On the terminal homologation of physiologically active peptides as a means of increasing stability in human serum--neurotensin, opiorphin, B27-KK10 epitope, NPY.

Abstract
The terminal homologation by CH(2) insertion into the peptides mentioned in the title is described. This involves replacement of the N-terminal amino acid residue by a β(2) - and of the C-terminal amino acid residue by a β(3) -homo-amino acid moiety (β(2) hXaa and β(3) hXaa, resp.; Fig. 1). In this way, the structure of the peptide chain from the N-terminal to the C-terminal stereogenic center is identical, and the modified peptide is protected against cleavage by exopeptidases (Figs. 2 and 3). Neurotensin (NT; 1) and its C-terminal fragment NT(8-13) are ligands of the G-protein-coupled receptors (GPCR) NT1, NT2, NT3, and NT analogs are promising tools to be used in cancer diagnostics and therapy. The affinities of homologated NT analogs, 2b-2e, for NT1 and NT2 receptors were determined by using cell homogenates and tumor tissues (Table 1); in the latter experiments, the affinities for the NT1 receptor are more or less the same as those of NT (0.5-1.3 vs. 0.6 nM). At the same time, one of the homologated NT analogs, 2c, survives in human plasma for 7 days at 37° (Fig. 6). An NMR analysis of NT(8-13) (Tables 2 and 4, and Fig. 8) reveals that this N-terminal NT fragment folds to a turn in CD(3) OH. - In the case of the human analgesic opiorphin (3a), a pentapeptide, and of the HIV-derived B27-KK10 (4a), a decapeptide, terminal homologation (→3b and 4b, resp.) led to a 7- and 70-fold half-life increase in plasma (Fig. 9). With N-terminally homologated NPY, 5c, we were not able to determine serum stability; the peptide consisting of 36 amino acid residues is subject to cleavage by endopetidases. Three of the homologated compounds, 2b, 2c, and 5c, were shown to be agonists (Fig. 7 and 11). A comparison of terminal homologation with other stability-increasing terminal modifications of peptides is performed (Fig. 5), and possible applications of the neurotensin analogs, described herein, are discussed.
AuthorsDieter Seebach, Aneta Lukaszuk, Krystyna Patora-Komisarska, Dominika Podwysocka, James Gardiner, Marc-Olivier Ebert, Jean Claude Reubi, Renzo Cescato, Beatrice Waser, Peter Gmeiner, Harald Hübner, Catherine Rougeot
JournalChemistry & biodiversity (Chem Biodivers) Vol. 8 Issue 5 Pg. 711-39 (May 2011) ISSN: 1612-1880 [Electronic] Switzerland
PMID21560227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Verlag Helvetica Chimica Acta AG, Zürich.
Chemical References
  • Neuropeptide Y
  • Oligopeptides
  • Receptors, Neurotensin
  • Salivary Proteins and Peptides
  • Viral Proteins
  • glutaminyl-arginyl-phenylalanyl-seryl-arginine
  • Neurotensin
  • Exopeptidases
Topics
  • Amino Acid Sequence
  • Biomimetic Materials (chemistry, metabolism)
  • Cell Line
  • Cell Line, Tumor
  • Exopeptidases (metabolism)
  • HIV (chemistry, metabolism)
  • Humans
  • Molecular Sequence Data
  • Neuropeptide Y (chemistry, metabolism)
  • Neurotensin (analogs & derivatives, metabolism)
  • Oligopeptides (chemistry, metabolism)
  • Protein Binding
  • Protein Stability
  • Receptors, Neurotensin (metabolism)
  • Salivary Proteins and Peptides (chemistry, metabolism)
  • Serum (metabolism)
  • Viral Proteins (chemistry, metabolism)

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