864084-88-8Relevant articles and documents
Structure-activity relationship study of opiorphin, a human dual ectopeptidase inhibitor with antinociceptive properties
Rosa, Mònica,Arsequell, Gemma,Rougeot, Catherine,Calle, Luis P.,Marcelo, Filipa,Pinto, Marta,Centeno, Nuria B.,Jiménez-Barbero, Jesús,Valencia, Gregorio
, p. 1181 - 1188 (2012)
Toward developing new potential analgesics, this first structure-activity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phe3 is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phe3-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue. Additional substituted Phe3 derivatives showed that replacing l-Phe3 for d-Phe3 increased the AP-N inhibition potency by 1 order of magnitude. NMR studies and molecular mechanics calculations indicated that the improved potency may be due to CH-π stacking interactions between the aromatic ring of d-Phe3 and the Hγ protons of Arg2. This structural motif is not possible for the native opiorphin and may be useful for the design of further potent and metabolically stable analogues.
The synthesis of opiorphin and studies on its binding ability toward Cu(II)
Kotynia, Aleksandra,Kamasz, Elzbieta,Czapor, Hanna,Brasuń, Justyna
, p. 2486 - 2488 (2010)
Opiorphin (OPI) is an endogenous pentapeptide isolated from human saliva. A characteristic feature of this peptide is the presence of an N-terminal Gln residue. The synthesis and binding abilities of opiorphin toward Cu(II) ions are described. The use of potentiometric and spectroscopic methods allows us to propose the binding mode of the formed complexes.
Influence of polar side chains modifications on the dual enkephalinase inhibitory activity and conformation of human opiorphin, a pain perception related peptide
Rosa, Mònica,Marcelo, Filipa,Calle, Luis P.,Rougeot, Catherine,Jiménez-Barbero, Jesús,Arsequell, Gemma,Valencia, Gregorio
supporting information, p. 5190 - 5193 (2015/11/09)
The dual inhibitory action of the pain related peptide opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH) against neutral endopeptidase (NEP) and aminopeptidase N (AP-N) was further investigated by a SAR study involving minor modifications on the polar side chains of Arg residues and glycosylation with monosaccharides at Ser. None of them exerted dual or individual inhibitory potency superior than opiorphin. However, the correlations deduced offer further proof for the key role of these residues upon the binding and bioactive conformational stabilization of opiorphin. NMR conformational studies on the glycopeptides suggest that they are still very flexible compounds that may attain their respective bioactive conformations.
On the terminal homologation of physiologically active peptides as a means of increasing stability in human serum - Neurotensin, opiorphin, B27-KK10 epitope, NPY
Seebach, Dieter,Lukaszuk, Aneta,Patora-Komisarska, Krystyna,Podwysocka, Dominika,Gardiner, James,Ebert, Marc-Olivier,Reubi, Jean Claude,Cescato, Renzo,Waser, Beatrice,Gmeiner, Peter,Huebner, Harald,Rougeot, Catherine
experimental part, p. 711 - 739 (2012/01/13)
The terminal homologation by CH2 insertion into the peptides mentioned in the title is described. This involves replacement of the N-terminal amino acid residue by a β2- and of the C-terminal amino acid residue by a β3-homo-amino acid moiety (β2hXaa and β3hXaa, 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. 0.6nM). 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 CD3OH. - 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. Copyright
