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Activity Study (activity + study)
Selected AbstractsStructure,Activity Study on the Spatial Arrangement of the Third Aromatic Ring of Endomorphins 1 and 2 Using an Atypical Constrained C,TerminusCHEMMEDCHEM, Issue 3 2007Ye Yu Dr. Abstract The discovery of endomorphins (EMs) has opened the possibility of searching for new analgesics. However, the design of peptide analgesics has proven to be very difficult as a result of their conformational flexibility and a lack of clarity in structure,activity relationships (SAR). In EMs, the amino acid side chains exhibit considerable conformational flexibility, especially in the third aromatic ring, which is free to adopt a bioactive conformation. To resolve these problems, a series of C,terminus EM analogues, [Xaa4 -R]EMs, modified through the substitution of Phe4 with nonaromatic residues and termination with benzyl groups, were designed to generate conformational constrains of the third aromatic ring by amide bond and torsion angles (,4 and ,4) of Xaa4. Introduction of (S)-,-methyl or (S)/(R)-,-carboxamide on the methylene unit of the benzyl group was designed to produce an atypical topographical constraint (,5) of the third aromatic ring rotation. Interestingly, some EM derivatives, with elimination of the C-terminal carboxamide group and significant changes in the address sequence (Phe4 -NH2), still exhibited higher ,-opioid receptor (MOR) affinity than unmodified EMs. In contrast, some analogues with incorrectly constrained C,termini displayed very low affinity and pharmacological activities. Thus, our results indicate that these EM analogues, with atypical constrained C,termini, provide model compounds with potent MOR agonism. They also give evidence that the proper spatial orientation and conformational restriction of the third aromatic ring are crucial for the interaction of EMs with MOR. [source] Pyrrolidino DNA with Bases Corresponding to the 2-Oxo Deletion Mutants of Thymine and Cytosine: Synthesis and Triplex-Forming PropertiesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 24 2007Alain Mayer Abstract The dual recognition properties of pyrrolidino DNA species as parallel triplex-forming oligonucleotides were previously found to be strongly dependent upon the nature of the pyrimidine bases. In the structure,activity study presented here we were able to exclude this differential binding being due to their 2-oxo function. We had previously reported on the incorporation of pyrrolidino C -nucleosides into triplex-forming 2,-deoxyoligonucleotides (TFOs). The basic nitrogen atom that replaces the 4,-oxygen atom of the 2,-deoxysugar in such modified units introduces a positive charge in the third strand, and this is able to produce favourable electrostatic interaction with the negatively charged DNA target duplex. A first series of pyrrolidino pseudonucleosides with the bases isocytosine and uracil proved successful for GC base-pair recognition, but was unsuccessful for AT base-pair recognition within the parallel triplex binding motif. Here we report on the synthesis of the two novel 2,-deoxypyrrolidino nucleosides carrying the bases pyridin-2-one and 2-aminopyridine, their phosphoramidite building blocks and theirincorporation into TFOs. Pyrrolidinylpyridin-2-one (dp2P) and -2-aminopyridine (dp2AP), prepared as part of a structure,activity profiling of pyrrolidino DNA in triplex binding, are deletion mutants of T and C, respectively. We found by Tm measurements that neither modification increased triplex binding efficiency relative to the iso-C- and -U-containing pyrrolidino TFOs. These experiments clearly show that the C4 carbonyl function, although important for triplex binding through indirect contributions in general, is not responsible for the differential binding of the latter two aminonucleosides and suggest that TFO conformation is more important. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Identification of crucial residues for the antibacterial activity of the proline-rich peptide, pyrrhocoricinFEBS JOURNAL, Issue 17 2002Goran Kragol Members of the proline-rich antibacterial peptide family, pyrrhocoricin, apidaecin and drosocin appear to kill responsive bacterial species by binding to the multihelical lid region of the bacterial DnaK protein. Pyrrhocoricin, the most potent among these peptides, is nontoxic to healthy mice, and can protect these animals from bacterial challenge. A structure,antibacterial activity study of pyrrhocoricin against Escherichia coli and Agrobacterium tumefaciens identified the N-terminal half, residues 2,10, the region responsible for inhibition of the ATPase activity, as the fragment that contains the active segment. While fluorescein-labeled versions of the native peptides entered E. coli cells, deletion of the C-terminal half of pyrrhocoricin significantly reduced the peptide's ability to enter bacterial or mammalian cells. These findings highlighted pyrrhocoricin's suitability for combating intracellular pathogens and raised the possibility that the proline-rich antibacterial peptides can deliver drug leads into mammalian cells. By observing strong relationships between the binding to a synthetic fragment of the target protein and antibacterial activities of pyrrhocoricin analogs modified at strategic positions, we further verified that DnaK was the bacterial target macromolecule. Inaddition, the antimicrobial activity spectrum of native pyrrhocoricin against 11 bacterial and fungal strains and the binding of labeled pyrrhocoricin to synthetic DnaK D-E helix fragments of the appropriate species could be correlated. Mutational analysis on a synthetic E. coli DnaK fragment identified a possible binding surface for pyrrhocoricin. [source] Development of a potent and selective GPR7 (NPBW1) agonist: a systematic structure,activity study of neuropeptide BJOURNAL OF PEPTIDE SCIENCE, Issue 6 2007Maki Kanesaka Abstract Neuropeptide B (NPB) has been recently identified as an endogenous ligand for GPR7 (NPBW1) and GPR8 (NPBW2) and has been shown to possess a relatively high selectivity for GPR7. In order to identify useful experimental tools to address physiological roles of GPR7, we synthesized a series of NPB analogs based on modification of an unbrominated form of 23 amino acids with amidated C -terminal, Br(,)NPB-23-NH2. We confirmed that truncation of the N -terminal Trp residue resulted in almost complete loss of the binding affinity of NPB for GPR7 and GPR8, supporting the special importance of this residue for binding. Br(,)NPB-23-NH2 analogs in which each amino acid in positions 4, 5, 7, 8, 9, 10, 12 and 21 was replaced with alanine or glycine exhibited potent binding affinity comparable to the parent peptide. In contrast, replacement of Tyr11 with alanine reduced the binding affinity for both GPR7 and GPR8 four fold. Of particular interest, several NPB analogs in which the consecutive amino acids from Pro4 to Val13 were replaced with several units of 5-aminovaleric acid (Ava) linkers retained their potent affinity for GPR7. Furthermore, these Ava-substituted NPB analogs exhibited potent agonistic activities for GPR7 expressed in HEK293 cells. Among the Ava-substituted NPB analogs, analog 15 (Ava-5) and 17 (Ava-3) exhibited potency comparable to the parent peptide for GPR7 with significantly reduced activity for GPR8, resulting in high selectivity for GPR7. These highly potent and selective NPB analogs may be useful pharmacological tools to investigate the physiological and pharmacological roles of GPR7. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] The relative orientation of the Arg and Asp side chains defined by a pseudodihedral angle as a key criterion for evaluating the structure,activity relationship of RGD peptidesJOURNAL OF PEPTIDE SCIENCE, Issue 8 2004Sarantos Kostidis Abstract The ability of an integrin to distinguish between the RGD-containing extracellular matrix proteins is thought to be due partially to the variety of RGD conformations. Three criteria have been proposed for the evaluation of the structure,activity relationship of RGD-containing peptides. These include: (i) the distance between the charged centres, (ii) the distance between the Arg C, and Asp C, atoms, and (iii) the pseudo-dihedral angle defining the Arg and Asp side-chain orientation formed by the Arg C,, Arg C,, Asp C, and Asp C, atoms. A comparative conformation,activity study was performed between linear RGD peptides and strongly constrained cyclic (S,S) -CDC- bearing compounds, which cover a wide range of inhibition potency of platelet aggregation. It is concluded that the fulfilment of the ,45° , pseudo-dihedral angle , +45° criterion is a prerequisite for an RGD compound to exhibit inhibitory activity. Once this criterion is accomplished, the longer the distance between the charged centres and/or between the Arg and Asp C, atoms, the higher is the biological activity. In addition, the stronger the ionic interaction between Arg and Asp charged side chains, the lower the anti-aggregatory activity. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source] Aggregation and surface-enhanced Raman activity study of dye-coated mixed silver,gold colloidsJOURNAL OF RAMAN SPECTROSCOPY, Issue 11 2004Jinghuai Fang Abstract The aggregate morphologies of silver, gold, and mixed silver,gold nanoparticles coated with fuchsine basic were directly investigated by means of transmission electron microscopy. It was found that the aggregation of silver and gold colloids induced by the adsorption of fuchsine basic displayed different aggregate characteristics. The adsorption of fuchsine basic in mixed silver and gold colloidal systems led to altered aggregation and surface-enhanced Raman scattering (SERS) enhancement behavior. A suitable ratio of mixed silver and gold colloids could form a favorable state of aggregation and significantly increase the SERS activity of mixed colloids compared with single silver and gold colloids. This is the first report of the SERS of fuchsine basic on mixed silver and gold colloids. Copyright © 2004 John Wiley & Sons, Ltd. [source] Comparative analysis of neonicotinoid binding to insect membranes: I. A structure,activity study of the mode of [3H]imidacloprid displacement in Myzus persicae and Aphis craccivoraPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 10 2004Dr Hartmut Kayser Abstract Neonicotinoids bind selectively to insect nicotinic acetylcholine receptors with nanomolar affinity to act as potent insecticides. While the members of the neonicotinoid class have many structural features in common, it is not known whether they also share the same mode of binding to the target receptor. Previous competition studies with [3H]imidacloprid, the first commercialised neonicotinoid, indicated that thiamethoxam, representing a novel structural sub-class, may bind in a different way from that of other neonicotinoids. In the present work we analysed the mode of [3H]imidacloprid displacement by established neonicotinoids and newly synthesized analogues in the aphids Myzus persicae Sulzer and Aphis craccivora Koch. We found two classes of neonicotinoids with distinct modes of interference with [3H]imidacloprid, described as direct competitive inhibition and non-competitive inhibition, respectively. Competitive neonicotinoids were acetamiprid, nitenpyram, thiacloprid, clothianidin and nithiazine, whereas thiamethoxam and the N -methyl analogues of imidacloprid and clothianidin showed non-competitive inhibition. The chloropyridine or chlorothiazole heterocycles, the polar pharmacophore parts, such as nitroimino, cyanoimino and nitromethylene, and the cyclic or acyclic structure of the pharmacophore were not relevant for the mode of inhibition. Consensus structural features of the neonicotinoids were defined for the two mechanisms of interaction with [3H]imidacloprid binding. Furthermore, two sub-classes of non-competitive inhibitors can be discriminated on the basis of their Hill coefficients for imidacloprid displacement. We conclude from the present data that the direct competitors share the binding site with imidacloprid, whereas non-competitive compounds, like thiamethoxam, bind to a different site or in a different mode. Copyright © 2004 Society of Chemical Industry [source] | ||||||||||