On the terminal homologation of physiologically active peptides as a means of increasing stability in human serum--neurotensin, opiorphin, B27-KK10 epitope, NPY
| Autor: | Beatrice Waser, Renzo Cescato, Dominika Jadwiga Podwysocka, Peter Gmeiner, Catherine Rougeot, Krystyna Patora-Komisarska, Dieter Seebach, Marc-Olivier Ebert, Jean Claude Reubi, James Gardiner, Harald Hübner, Aneta Lukaszuk |
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| Rok vydání: | 2011 |
| Předmět: |
Serum
Peptidomimetic Stereochemistry Molecular Sequence Data Bioengineering Peptide Biochemistry Pentapeptide repeat Cell Line chemistry.chemical_compound Viral Proteins Biomimetic Materials Cell Line Tumor Exopeptidases medicine Humans Receptors Neurotensin Neuropeptide Y Amino Acid Sequence Salivary Proteins and Peptides Molecular Biology Peptide sequence Neurotensin chemistry.chemical_classification Oligopeptide biology Chemistry Protein Stability Opiorphin HIV General Chemistry General Medicine Exopeptidase biology.protein Molecular Medicine Oligopeptides medicine.drug Protein Binding |
| Zdroj: | Chemistrybiodiversity. 8(5) |
| ISSN: | 1612-1880 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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