ABSTRACT
Several natural peptides have a biaryl or biaryl ether motif in their biologically active structures. A model bicyclic pentapeptide containing a biaryl bridge has been synthesized by solid-phase peptide synthesis combining on-resin Suzuki and Miyaura cross-coupling reactions. Its biological properties in terms of permeability, stability and cytotoxicity have been studied, demonstrating the positive contribution of the biaryl bridge, excellent membrane penetration and serum stability Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Subject(s)
Biological Products/chemistry , Oligopeptides/chemistry , Biological Products/blood , Biological Products/chemical synthesis , Biological Products/toxicity , Cell Survival/drug effects , Dose-Response Relationship, Drug , HeLa Cells , Humans , Molecular Conformation , Oligopeptides/blood , Oligopeptides/chemical synthesis , Oligopeptides/toxicity , Solid-Phase Synthesis Techniques , Structure-Activity RelationshipABSTRACT
Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia.
Subject(s)
Cognition Disorders/drug therapy , Proline/analogs & derivatives , Psychotropic Drugs/pharmacology , Schizophrenia/drug therapy , Schizophrenic Psychology , Animals , Cell Line, Tumor , Cognition/drug effects , Cognition/physiology , Cognition Disorders/enzymology , Cognition Disorders/etiology , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice, Inbred C57BL , Motor Activity/drug effects , Motor Activity/physiology , Poly I-C , Prepulse Inhibition/drug effects , Prepulse Inhibition/physiology , Proline/chemistry , Proline/pharmacokinetics , Proline/pharmacology , Proline/toxicity , Prolyl Oligopeptidases , Psychotropic Drugs/chemistry , Psychotropic Drugs/pharmacokinetics , Psychotropic Drugs/toxicity , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Schizophrenia/complications , Schizophrenia/enzymology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/toxicityABSTRACT
Schizophrenia is a serious life-long disease that affects a significant part of the adult population. Although there is considerably effective medication for the positive symptoms of the disease, none are available for the associated cognitive deficits. These deficits are a core feature of schizophrenia, and they severely impair the functionality and social integration of patients. POP is a promising target for the treatment of the cognitive deficits of schizophrenia. Inhibitors of this peptidase show cognition-enhancing properties, act through a complex mechanism and have suitable pharmacological properties. Nevertheless, several studies must be carried out in order to improve the design and clinical evaluation of these substances. Permeability to the brain, appropriate animal models and suitable indications are the main issues that must be addressed. However, current information supports the potential of POP as an interesting drug target for the treatment of the cognitive deficits related to schizophrenia.
Subject(s)
Schizophrenia/drug therapy , Schizophrenia/enzymology , Serine Proteases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/therapeutic use , Animals , Drug Discovery/methods , Humans , Molecular Targeted Therapy/methods , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Peptidomimetics/therapeutic use , Serine Proteinase Inhibitors/pharmacologyABSTRACT
[Structure: see text] The self-assembly in the crystal state of the terminally protected, linear dipeptide Boc-(S,S)c3diPhe-(R,R)c3diPhe-NHiPr (1) through intermolecular hydrogen bonds leads to the formation of a supramolecular helix of large diameter (18 A), internally decorated with phenyl rings. As a result, a hollow helical channel large enough to accommodate guest molecules is observed. This supramolecular structure differs from previous examples of peptide nanotubes. Compound 1 incorporates a highly restricted cyclopropane phenylalanine analogue (c3diPhe) with remarkable conformational properties.
Subject(s)
Nanotubes, Peptide , Crystallization , Models, Molecular , X-Ray DiffractionABSTRACT
Terminally blocked, homo-peptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c3diPhe), a chiral member of the family of Calpha-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-c3diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where c3diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that c3diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)-helix conformations. However, when c3diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed.
Subject(s)
Cyclopropanes/chemistry , Peptide Fragments/chemistry , Phenylalanine/chemistry , Circular Dichroism , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Models, Chemical , Models, Molecular , Protein Conformation , Spectroscopy, Fourier Transform InfraredABSTRACT
We have examined the preferred 3D structure of homopeptides based on an alpha-amino acid lacking the asymmetry at the alpha-carbon but exhibiting chirality in the side chains (at the two beta-carbons). These joint stereochemical properties are remarkably unusual for an alpha-amino acid. To this end, we carried out an experimental investigation by X-ray diffraction and NMR spectrometry. The results point to a well-defined relationship between screw sense of the turn and helix structures formed and side-chain configurations.
Subject(s)
Cyclopropanes/chemistry , Peptides/chemistry , Models, Molecular , Protein Structure, Secondary , Stereoisomerism , X-Ray DiffractionABSTRACT
A strategy for the preparation of enantiomerically pure (R)- and (S)-alpha-methyldiphenylalanine, constrained phenylalanine analogs, is described. A racemic precursor was prepared in high yield from easily available starting products and subjected to HPLC resolution on a noncommercial chiral stationary phase. More than 600 mg of each enantiomer was isolated in optically pure form by using a 150 x 20 mm ID column containing mixed 10-undecenoate/3,5-dimethylphenylcarbamate of cellulose covalently bonded to allylsilica gel and a mixture of n-hexane/2-propanol/acetone as the mobile phase.
