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31.
A Hot‐Segment‐Based Approach for the Design of Cross‐Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self‐Assembly
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Dr. Erika Andreetto Dipl.‐Chem. Eleni Malideli Dr. Li‐Mei Yan Dipl.‐Ing. Michael Kracklauer MSc. Karine Farbiarz Dipl.‐Chem. Marianna Tatarek‐Nossol Prof. Dr. Gerhard Rammes M. Sc. Elke Prade Tatjana Neumüller Dr. Andrea Caporale M. Sc. Anna Spanopoulou B. Sc. Maria Bakou Prof. Dr. Bernd Reif Prof. Dr. Aphrodite Kapurniotu 《Angewandte Chemie (International ed. in English)》2015,54(44):13095-13100
The design of inhibitors of protein–protein interactions mediating amyloid self‐assembly is a major challenge mainly due to the dynamic nature of the involved structures and interfaces. Interactions of amyloidogenic polypeptides with other proteins are important modulators of self‐assembly. Here we present a hot‐segment‐linking approach to design a series of mimics of the IAPP cross‐amyloid interaction surface with Aβ (ISMs) as nanomolar inhibitors of amyloidogenesis and cytotoxicity of Aβ, IAPP, or both polypeptides. The nature of the linker determines ISM structure and inhibitory function including both potency and target selectivity. Importantly, ISMs effectively suppress both self‐ and cross‐seeded IAPP self‐assembly. Our results provide a novel class of highly potent peptide leads for targeting protein aggregation in Alzheimer’s disease, type 2 diabetes, or both diseases and a chemical approach to inhibit amyloid self‐assembly and pathogenic interactions of other proteins as well. 相似文献
32.
Ta HP Berthelot K Coulary-Salin B Desbat B Géan J Servant L Cullin C Lecomte S 《Langmuir : the ACS journal of surfaces and colloids》2011,27(8):4797-4807
Many in vitro studies have pointed out the interaction between amyloids and membranes, and their potential involvement in amyloid toxicity. In a previous study, we generated a yeast toxic mutant (M8) of the harmless model amyloid protein HET-s((218-289)). In this study, we compared the self-assembling process of the nontoxic wild-type (WT) and toxic (M8) protein at the air-water interface and in interaction with various phospholipid monolayers (DOPE, DOPC, DOPI, DOPS and DOPG). We first demonstrate using ellipsometry measurements and polarization-modulated infrared reflection absorption spectroscopy (PMIRRAS) that the air-water interface promotes and modifies the assembly of WT since an amyloid-like film was instantaneously formed at the interface with an antiparallel β-sheet structuration instead of the parallel β-sheet commonly observed for amyloid fibers generated in solution. The toxic mutant (M8) behaves in a similar manner at the air-water interface or in bulk, with a fast self-assembling and an antiparallel β-sheet organization. The transmission electron microscopy (TEM) images established the fibrillous morphology of the protein films formed at the air-water interface. Second, we demonstrate for the first time that the main driving force between this particular fungus amyloid and membrane interaction is based on electrostatic interactions with negatively charged phospholipids (DOPG, DOPI, DOPS). Interestingly, the toxic mutant (M8) clearly induces perturbations of the negatively charged phospholipid monolayers, leading to a massive surface aggregation, whereas the nontoxic (WT) exhibits a slight effect on the membrane models. This study allows concluding that the toxicity of the M8 mutant could be due to its high propensity to interact with membranes. 相似文献
33.
A convenient synthesis of 4'-aminopantetheine from commercial D-pantethine is reported. The amino group was introduced by reductive amination in order to avoid substitution at a sterically congested position. Derivatives of 4'-aminopantetheine were also prepared to evaluate the effect of O-to-N substitution on inhibitors of the resistance-causing enzyme aminoglycoside N-6'-acetyltransferase. The biological results combined with docking studies indicate that in spite of its reported unusual flexibility and ability to adopt different folds, this enzyme is highly specific for AcCoA. 相似文献
34.
Much effort has been made during the last decade to design lectin inhibitors as therapeutics against viral and bacterial adhesion or to control biological functions. The chemical strategy adopted generally consists in the tethering of several binding epitopes on a common scaffold. The resulting multivalent glycoconjugates often display a much higher binding affinity for their targets compared to their monovalent counterparts, a phenomenon designed as the "cluster" or "multivalent effect". Hundreds of multimeric architectures have been designed so far and some of the compounds displayed impressive gains in binding affinity or in vivo efficiency. Progress in this area is, however, hampered by the difficulty to predict the potency of the new multimeric inhibitors. This review presents the recent efforts to probe the important structural features of the synthetic multivalent glycoconjugates for a tight binding with specific lectins. We hope that the reported examples will aid the reader to design efficient multivalent ligands in a more predictable way. 相似文献
35.
Karine Beauchard 《Journal of Differential Equations》2011,250(4):2064-2098
We consider a linear wave equation, on the interval (0,1), with bilinear control and Neumann boundary conditions. We study the controllability of this nonlinear control system, locally around a constant reference trajectory. We prove that the following results hold generically.
- •
- For every T>2, this system is locally controllable in H3×H2, in time T, with controls in L2((0,T),R).
- •
- For T=2, this system is locally controllable up to codimension one in H3×H2, in time T, with controls in L2((0,T),R): the reachable set is (locally) a non-flat submanifold of H3×H2 with codimension one.
- •
- For every T<2, this system is not locally controllable, more precisely, the reachable set, with controls in L2((0,T),R), is contained in a non-flat submanifold of H3×H2, with infinite codimension.
36.
Nagy K Redeuil K Williamson G Rezzi S Dionisi F Longet K Destaillats F Renouf M 《Journal of chromatography. A》2011,1218(3):491-497
There is a substantial amount of published literature on the bioavailability of various coffee components including the most abundant metabolites, caffeic and ferulic acids. Surprisingly, to date, the appearance of dimethoxycinnamic acid derivatives in humans has not been reported despite the fact that methylated form of catechol-type polyphenols could help maintain, modify or even improve their biological activities. This study reports an LC-MS method for the detection of dimethoxycinnamic acid in human plasma after treatment with an esterase. Liquid chromatography, including the combination of methanol and acetonitrile as organic eluent, was optimized to resolve all interferences and enable reliable detection and identification of 3,4-dimethoxycinnamic and 3,4-dimethoxy-dihydrocinnamic acids. In addition to the good mass accuracy achieved (better than 5 ppm), tandem mass spectrometric and co-chromatography experiments further confirmed the identity of the compounds. The optimized method was applied to analyze samples obtained immediately, 1 and 10 h after coffee ingestion. The results show that in particular 3,4-dimethoxycinnamic acid appears in high abundance (~380 nM at 60 min) in plasma upon coffee intake, indicating that it is important to consider these derivatives in future bioavailability and bioefficacy studies. 相似文献
37.
Costuas K Cador O Justaud F Le Stang S Paul F Monari A Evangelisti S Toupet LC Lapinte C Halet JF 《Inorganic chemistry》2011,50(24):12601-12622
The role of the nitrogen atom on the electronic and magnetic couplings of the mono-oxidized and bi-oxidized pyridine-containing complex models [2,6-{Cp(dpe)Fe-C≡C-}(2)(NC(5)H(3))](n+) and [3,5-{Cp(dpe)Fe-C≡C-}(2)(NC(5)H(3))](n+) is theoretically tackled with the aid of density-functional theory (DFT) and multireference configuration interaction (MR-CI) calculations. Results are analyzed and compared to those obtained for the reference complex [1,3-{Cp*(dppe)Fe-C≡C-)}(2)(C(6)H(4))](n+). The mono-oxidized species show an interesting behavior at the borderline between spin localization and delocalization and one through-bond communication path among the two involving the central ring, is favored. Investigation of the spin state of the dicationic complexes indicates ferromagnetic coupling, which can differ in magnitude from one complex to the other. Very importantly, electronic and magnetic properties of these species strongly depend not only upon the location of the nitrogen atom in the ring versus that of the organometallic end-groups but also upon the architectural arrangement of one terminus, with respect to the other and/or vis-à-vis the central ring. To help validate the theoretical results, the related families of compounds [1,3-{Cp*(dppe)Fe-C≡C-)}(2)(C(6)H(4))](n+), [2,6-{Cp*(dppe)Fe-C≡C-}(2)(NC(5)H(3))](n+), [3,5-{Cp*(dppe)Fe-C≡C-}(2)(NC(5)H(3))](n+) (n = 0-2) were experimentally synthesized and characterized. Electrochemical, spectroscopic (infrared (IR), M?ssbauer), electronic (near-infrared (NIR)), and magnetic properties (electron paramagnetic resonance (EPR), superconducting quantum interference device (SQUID)) are discussed and interpreted in the light of the theoretical data. The set of data obtained allows for many strong conclusions to be drawn. A N atom in the long branch increases the ferromagnetic interaction between the two Fe(III) spin carriers (J > 500 cm(-1)), whereas, when placed in the short branch, it dramatically reduces the magnetic exchange in the di-oxidized species (J = 2.14(5) cm(-1)). In the mixed-valence compounds, when the N atom is positioned on the long branch, the intermediate excited state is higher in energy than the different ground-state conformers and the relaxation process provides exclusively the Fe(II)/Fe(III) localized system (H(ab) ≠ 0). Positioning the N atom on the short branch modifies the energy profile and the diabatic mediating state lies just above the reactant and product diabatic states. Consequently, the LMCT transition becomes less energetic than the MMCT transition. Here, the direct coupling does not occur (H(ab) = 0) and only the coupling through the bridge (c) and the reactant (a) and product (b) diabatic states is operating (H(ac) = H(bc) ≠ 0). 相似文献
38.
39.
Salas G Podgoršek A Campbell PS Santini CC Pádua AA Costa Gomes MF Philippot K Chaudret B Turmine M 《Physical chemistry chemical physics : PCCP》2011,13(30):13527-13536
Ionic liquids are a stabilizing medium for the in situ synthesis of ruthenium nanoparticles. Herein we show that the addition of molecular polar solutes to the ionic liquid, even in low concentrations, eliminates the role of the ionic liquid 3D structure in controlling the size of ruthenium nanoparticles, and can induce their aggregation. We have performed the synthesis of ruthenium nanoparticles by decomposition of [Ru(COD)(COT)] in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(4)Im][NTf(2)], under H(2) in the presence of varying amounts of water or 1-octylamine. For water added during the synthesis of metallic nanoparticles, a decrease of the solubility in the ionic liquid was observed, showed by nanoparticles located at the interface between aqueous and ionic phases. When 1-octylamine is present during the synthesis, stable nanoparticles of a constant size are obtained. When 1-octylamine is added after the synthesis, aggregation of the ruthenium nanoparticles is observed. In order to explain these phenomena, we have explored the molecular interactions between the different species using (13)C-NMR and DOSY (Diffusional Order Spectroscopy) experiments, mixing calorimetry, surface tension measurements and molecular simulations. We conclude that the behaviour of the ruthenium nanoparticles in [C(1)C(4)Im][NTf(2)] in the presence of 1-octylamine depends on the interaction between the ligand and the nanoparticles in terms of the energetics but also of the structural arrangement of the amine at the nanoparticle's surface. 相似文献
40.