the unusual metal ion binding ability of histidyl tags and their mutated derivatives

Peptides that consist of repeated sequences of alternating histidines and alanines strongly bind Cu(ii) and form α-helical structures

Performance Assessment in Fingerprinting and Multi Component Quantitative NMR Analyses

An interlaboratory comparison (ILC) was organized with the aim to set up quality control indicators suitable for multicomponent quantitative analysis by nuclear magnetic resonance (NMR) spectroscopy. A total of 36 NMR data sets (corresponding to 1260 NMR spectra) were produced by 30 participants using 34 NMR spectrometers. The calibration line method was chosen for the quantification of a five-component model mixture. Results show that quantitative NMR is a robust quantification tool and that 26 out of 36 data sets resulted in statistically equivalent calibration lines for all considered NMR signals. The performance of each laboratory was assessed by means of a new performance index (named Qp-score) which is related to the difference between the experimental and the consensus values of the slope of the calibration lines. Laboratories endowed with a Qp-score falling within the suitable acceptability range are qualified to produce NMR spectra that can be considered statistically equivalent in terms of relative intensities of the signals. In addition, the specific response of nuclei to the experimental excitation/relaxation conditions was addressed by means of the parameter named NR. NR is related to the difference between the theoretical and the consensus slopes of the calibration lines and is specific for each signal produced by a well-defined set of acquisition parameters

Synthesis, structural characterization and pharmacological evaluation of spiroxatrine analogs as potential nociceptin/orphanin FQ receptor ligands

The nociceptin/Orphanin FQ (N/OFQ) peptide (NOP) receptor is a G protein-coupled receptor with a high degree of structural homology (~ 60%) to the classical opioid receptors μ, δ and κ. The interaction between NOPand its endogenous agonist N/OFQ plays a key role in pain transmission, among other biological functions. Therefore, this system opened a new option for the treatment of acute and chronic pain possibly by generating drugs with a lower side effect profile.The confirmed affinity towards NOP receptor of the α2 adrenergic and 5-HT1A partial agonist spiroxatrine (Ki= 127 nM) has led us to the synthesis of a series of novel and optimized analogs based upon the spiropiperidinecore, in order to perform preliminarySAR studies

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Zn(II) and Ni(II) complexes with poly-histidyl peptides derived from a snake venom

The snake venoms are complex mixtures containing many bioactive peptides and proteins; some of them are aimed to protect the snake glands, where the venom is stored, until the latter is inoculated in the victim. In the venom of some vipers of the genus Atheris, a set of peptides containing poly-His and poly-Gly segments was recently found. Poly-His peptides are not rare in Nature. Although their exact biological function is most often unknown, one thing is certain: they have good binding properties towards the transition metal ions. As a matter of fact, the imidazole side chain of histidine is one of the groups most frequently involved in metal complexation in the active sites of metallo-enzymes. This is also true for snake-venom metallo-proteases, which contain Zn(II) and Ca(II) ions.In the present paper, the complex-formation ability of the poly-His-poly-Gly peptide found in the venom of Atheris squamigera (EDDH9GVG10-NH2) towards the Zn(II) and Ni(II) ions was investigated by means of thermodynamic and spectroscopic techniques. Two model peptides, derived from the poly-His portion of this peptide but where His residues were alternated with alanines (Ac-EDDAHAHAHAHAG-NH2, and Ac-EDDHAHAHAHAHG-NH2) were also studied, for the sake of comparison. The high affinity of these peptides for the metal ions under investigation was confirmed. In addition, it was demonstrated that the number of His residues in the peptide and their relative position play a main role in the complex-formation ability of the ligand. The very high affinity of EDDH9GVG10-NH2 for Zn(II) can be the key for its role in the inactivation of the venom in the snake glands

1,4-Dioxolane-triazaspirodecanone derivatives as nociceptin/orphanin FQ receptor ligands

A series of N-substituted analogs based upon the spiropiperidine core of the lead compound Spiroxatrine was synthesized. In particular, the new compounds were obtained by replacing the benzodioxane moiety of the Spiroxatrine with several 2-substituted 1,3-dioxolanes. Thus the designed derivatives were synthesized and evaluated as possible NOP receptor ligands. As a conclusion of these studies, the new triazaspirodecanone derivatives showed unique and significant SAR as NOP receptor agonists. In particular, the present study demonstrated that 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one portion together with appropriate 1,3-dioxolane substituents could lead to a new promising class of NOP receptor ligands

Synthesis, enantiomeric separation and docking studies of spiropiperidine analogues as ligands of the nociceptin/orphanin FQ receptor

A series of triazospirodecanone derivatives were synthesized as potential NOP ligands. 8-(Chroman-4-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (4) and its 5-fluoro analogue (18) proved to be active as agonists with EC50 values in the submicromolar range. Single enantiomers of compound 4 were separated and tested as NOP agonists; the eutomer R-(+)-4 showed a pEC50 of 7.34. Finally docking studies were performed on the NOP receptor to identify the most significant stereospecific interactions