共查询到20条相似文献,搜索用时 15 毫秒
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Dr. Li‐Mei Yan Dr. Aleksandra Velkova Dipl.‐Chem. Marianna Tatarek‐Nossol Prof. Dr. Gerhard Rammes Dr. Andrei Sibaev Dr. Erika Andreetto Dipl.‐Ing. Michael Kracklauer Dipl.‐Biochem. Maria Bakou Dipl.‐Chem. Eleni Malideli Prof. Dr. Burkhard Göke Prof. Dr. Jörg Schirra Prof. Dr. Martin Storr Prof. Dr. Aphrodite Kapurniotu 《Angewandte Chemie (International ed. in English)》2013,52(39):10378-10383
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A Method for Evaluating the Level of Soluble β‐Amyloid(1–40/1–42) in Alzheimer’s Disease Based on the Binding of Gelsolin to β‐Amyloid Peptides 下载免费PDF全文
Dr. Yanyan Yu Lin Zhang Dr. Chenglin Li Xiaoyu Sun Dr. Daoquan Tang Prof. Guoyue Shi 《Angewandte Chemie (International ed. in English)》2014,53(47):12832-12835
In the present work, a new electrochemical strategy for the sensitive and specific detection of soluble β‐amyloid Aβ(1–40/1–42) peptides in a rat model of Alzheimer’s disease (AD) is described. In contrast to previous antibody‐based methods, β‐amyloid(1–40/1–42) was quantified based on its binding to gelsolin, a secretory protein present in the cerebrospinal fluid (CSF) and plasma. The level of soluble β‐amyloid peptides in the CSF and various brain regions were found with this method to be lower in rats with AD than in normal rats. 相似文献
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Dr. Christofer Lendel Dr. Morten Bjerring Dr. Anatoly Dubnovitsky Robert T. Kelly Dr. Andrei Filippov Prof. Dr. Oleg N. Antzutkin Prof. Dr. Niels Chr. Nielsen Prof. Dr. Torleif Härd 《Angewandte Chemie (International ed. in English)》2014,53(47):12756-12760
Oligomeric and protofibrillar aggregates formed by the amyloid‐β peptide (Aβ) are believed to be involved in the pathology of Alzheimer’s disease. Central to Alzheimer pathology is also the fact that the longer Aβ42 peptide is more prone to aggregation than the more prevalent Aβ40. Detailed structural studies of Aβ oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of Aβ that forms stable protofibrils and here we use solid‐state NMR spectroscopy and molecular modeling to derive a structural model of these. NMR data are consistent with packing of residues 16 to 42 of Aβ protomers into hexameric barrel‐like oligomers within the protofibril. The core of the oligomers consists of all residues of the central and C‐terminal hydrophobic regions of Aβ, and hairpin loops extend from the core. The model accounts for why Aβ42 forms oligomers and protofibrils more easily than Aβ40. 相似文献
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The Molecular Structure of Alzheimer β‐Amyloid Fibrils Formed in the Presence of Phospholipid Vesicles 下载免费PDF全文
Zheng Niu Weijing Zhao Dr. Zhengfeng Zhang Dr. Fanshu Xiao Xinqi Tang Prof. Jun Yang 《Angewandte Chemie (International ed. in English)》2014,53(35):9294-9297
β‐amyloid (Aβ) fibrils are the major species involved in Alzheimer’s disease (AD). An atomic‐resolution molecular structure of Aβ40 fibrils formed in the presence of lipid vesicles was obtained by using magic angle spinning (MAS) solid‐state NMR spectroscopy. The fibril structures formed in the presence of the lipid vesicles are remarkably different from those formed in solution. These results provide insights into the molecular mechanism of Aβ aggregation in the presence of lipid vesicles. 相似文献
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Characterizing Methyl‐Bearing Side Chain Contacts and Dynamics Mediating Amyloid β Protofibril Interactions Using 13Cmethyl‐DEST and Lifetime Line Broadening 下载免费PDF全文
Dr. Nicolas L. Fawzi Dr. David S. Libich Dr. Jinfa Ying Dr. Vitali Tugarinov Dr. G. Marius Clore 《Angewandte Chemie (International ed. in English)》2014,53(39):10345-10349
Many details pertaining to the formation and interactions of protein aggregates associated with neurodegenerative diseases are invisible to conventional biophysical techniques. We recently introduced 15N dark‐state exchange saturation transfer (DEST) and 15N lifetime line‐broadening to study solution backbone dynamics and position‐specific binding probabilities for amyloid β (Aβ) monomers in exchange with large (2–80 MDa) protofibrillar Aβ aggregates. Here we use 13Cmethyl DEST and lifetime line‐broadening to probe the interactions and dynamics of methyl‐bearing side chains in the Aβ‐protofibril‐bound state. We show that all methyl groups of Aβ40 populate direct‐contact bound states with a very fast effective transverse relaxation rate, indicative of side‐chain‐mediated direct binding to the protofibril surface. The data are consistent with position‐specific enhancements of 13Cmethyl‐${R{{{\rm tethered}\hfill \atop 2\hfill}}}$ values in tethered states, providing further insights into the structural ensemble of the protofibril‐bound state. 相似文献
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Delineating the Role of Helical Intermediates in Natively Unfolded Polypeptide Amyloid Assembly and Cytotoxicity 下载免费PDF全文
Carole Anne De Carufel Noé Quittot Phuong Trang Nguyen Prof. Steve Bourgault 《Angewandte Chemie (International ed. in English)》2015,54(48):14383-14387
Amyloid deposition is a hallmark of many diseases, such as the Alzheimer’s disease. Numerous amyloidogenic proteins, including the islet amyloid polypeptide (IAPP) associated with type II diabetes, are natively unfolded and need to undergo conformational rearrangements allowing the formation of locally ordered structure(s) to initiate self‐assembly. Recent studies have indicated that the formation of α‐helical intermediates accelerates fibrillization, suggesting that these species are on‐pathway to amyloid assembly. By identifying an IAPP derivative with a restricted conformational ensemble that co‐assembles with IAPP, we observed that helical species were off‐pathway in homogenous environment and in presence of lipid bilayers or glycosaminoglycans. Moreover, preventing helical folding potentiated membrane perturbation and IAPP cytotoxicity, indicating that stabilization of helical motif(s) is a promising strategy to prevent cell degeneration associated with amyloidogenesis. 相似文献
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Sara Santi Dr. Valeria Musi Dr. Emiliano Descrovi Dr. Vincent Paeder Joab Di Francesco Dr. Lubos Hvozdara Dr. Peter van der Wal Prof. Hilal A. Lashuel Prof. Annalisa Pastore Prof. Reinhard Neier Prof. Hans Peter Herzig 《Chemphyschem》2013,14(15):3476-3482
We propose the application of a new label‐free optical technique based on photonic nanostructures to real‐time monitor the amyloid‐beta 1‐42 (Aβ(1‐42)) fibrillization, including the early stages of the aggregation process, which are related to the onset of the Alzheimer’s Disease (AD). The aggregation of Aβ peptides into amyloid fibrils has commonly been associated with neuronal death, which culminates in the clinical features of the incurable degenerative AD. Recent studies revealed that cell toxicity is determined by the formation of soluble oligomeric forms of Aβ peptides in the early stages of aggregation. At this phase, classical amyloid detection techniques lack in sensitivity. Upon a chemical passivation of the sensing surface by means of polyethylene glycol, the proposed approach allows an accurate, real‐time monitoring of the refractive index variation of the solution, wherein Aβ(1‐42) peptides are aggregating. This measurement is directly related to the aggregation state of the peptide throughout oligomerization and subsequent fibrillization. Our findings open new perspectives in the understanding of the dynamics of amyloid formation, and validate this approach as a new and powerful method to screen aggregation at early stages. 相似文献
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Constrained Peptides with Target‐Adapted Cross‐Links as Inhibitors of a Pathogenic Protein–Protein Interaction 下载免费PDF全文
Dr. Gernot Hahne Dr. Christoph Rademacher Dr. Christian Ottmann Dr. Tom N. Grossmann 《Angewandte Chemie (International ed. in English)》2014,53(9):2489-2493
Bioactive conformations of peptides can be stabilized by macrocyclization, resulting in increased target affinity and activity. Such macrocyclic peptides proved useful as modulators of biological functions, in particular as inhibitors of protein–protein interactions (PPI). However, most peptide‐derived PPI inhibitors involve stabilized α‐helices, leaving a large number of secondary structures unaddressed. Herein, we present a rational approach towards stabilization of an irregular peptide structure, using hydrophobic cross‐links that replace residues crucially involved in target binding. The molecular basis of this interaction was elucidated by X‐ray crystallography and isothermal titration calorimetry. The resulting cross‐linked peptides inhibit the interaction between human adaptor protein 14‐3‐3 and virulence factor exoenzyme S. Taking into consideration that irregular peptide structures participate widely in PPIs, this approach provides access to novel peptide‐derived inhibitors. 相似文献
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Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes 下载免费PDF全文
Dr. Marta Pelay‐Gimeno Adrian Glas Dr. Oliver Koch Dr. Tom N. Grossmann 《Angewandte Chemie (International ed. in English)》2015,54(31):8896-8927
Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure‐based design of PPI inhibitors through stabilizing or mimicking turns, β‐sheets, and helices. 相似文献
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Gallotannins and Tannic Acid: First Chemical Syntheses and In Vitro Inhibitory Activity on Alzheimer’s Amyloid β‐Peptide Aggregation 下载免费PDF全文
Dr. Tahiri Sylla Prof. Laurent Pouységu Dr. Grégory Da Costa Dr. Denis Deffieux Prof. Jean‐Pierre Monti Prof. Stéphane Quideau 《Angewandte Chemie (International ed. in English)》2015,54(28):8217-8221
The screening of natural products in the search for new lead compounds against Alzheimer’s disease has unveiled several plant polyphenols that are capable of inhibiting the formation of toxic β‐amyloid fibrils. Gallic acid based gallotannins are among these polyphenols, but their antifibrillogenic activity has thus far been examined using “tannic acid”, a commercial mixture of gallotannins and other galloylated glucopyranoses. The first total syntheses of two true gallotannins, a hexagalloylglucopyranose and a decagalloylated compound whose structure is commonly used to depict “tannic acid”, are now described. These depsidic gallotannins and simpler galloylated glucose derivatives all inhibit amyloid β‐peptide (Aβ) aggregation in vitro, and monogalloylated α‐glucogallin and a natural β‐hexagalloylglucose are shown to be the strongest inhibitors. 相似文献
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Interaction of PiB‐Derivative Metal Complexes with Beta‐Amyloid Peptides: Selective Recognition of the Aggregated Forms 下载免费PDF全文
Dr. André F. Martins David M. Dias Dr. Jean‐François Morfin Dr. Sara Lacerda Dr. Douglas V. Laurents Dr. Éva Tóth Prof. Carlos F. G. C. Geraldes 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(14):5413-5422
Metal complexes are increasingly explored as imaging probes in amyloid peptide related pathologies. We report the first detailed study on the mechanism of interaction between a metal complex and both the monomer and the aggregated form of Aβ1–40 peptide. We have studied lanthanide(III) chelates of two PiB‐derivative ligands (PiB=Pittsburgh compound B), L1 and L2, differing in the length of the spacer between the metal‐complexing DO3A macrocycle (DO3A= 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid) and the peptide‐recognition PiB moiety. Surface plasmon resonance (SPR) and saturation transfer difference (STD) NMR spectroscopy revealed that they both bind to aggregated Aβ1–40 (KD=67–160 μM ), primarily through the benzothiazole unit. HSQC NMR spectroscopy on the 15N‐labeled, monomer Aβ1–40 peptide indicates nonsignificant interaction with monomeric Aβ. Time‐dependent circular dichroism (CD), dynamic light scattering (DLS), and TEM investigations of the secondary structure and of the aggregation of Aβ1–40 in the presence of increasing amounts of the metal complexes provide coherent data showing that, despite their structural similarity, the two complexes affect Aβ fibril formation distinctly. Whereas GdL1, at higher concentrations, stabilizes β‐sheets, GdL2 prevents aggregation by promoting α‐helical structures. These results give insight into the behavior of amyloid‐targeted metal complexes in general and contribute to a more rational design of metal‐based diagnostic and therapeutic agents for amyloid‐ associated pathologies. 相似文献
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Maintenance of Amyloid β Peptide Homeostasis by Artificial Chaperones Based on Mixed‐Shell Polymeric Micelles 下载免费PDF全文
Fan Huang Jianzu Wang Aoting Qu Liangliang Shen Dr. Jinjian Liu Jianfeng Liu Dr. Zhenkun Zhang Yingli An Prof. Linqi Shi 《Angewandte Chemie (International ed. in English)》2014,53(34):8985-8990
The disruption of Aβ homeostasis, which results in the accumulation of neurotoxic amyloids, is the fundamental cause of Alzheimer’s disease (AD). Molecular chaperones play a critical role in controlling undesired protein misfolding and maintaining intricate proteostasis in vivo. Inspired by a natural molecular chaperone, an artificial chaperone consisting of mixed‐shell polymeric micelles (MSPMs) has been devised with tunable surface properties, serving as a suppressor of AD. Taking advantage of biocompatibility, selectivity toward aberrant proteins, and long blood circulation, these MSPM‐based chaperones can maintain Aβ homeostasis by a combination of inhibiting Aβ fibrillation and facilitating Aβ aggregate clearance and simultaneously reducing Aβ‐mediated neurotoxicity. The balance of hydrophilic/hydrophobic moieties on the surface of MSPMs is important for their enhanced therapeutic effect. 相似文献
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Dr. Vijaya B. Kenche Dr. Lin W. Hung Keyla Perez Irene Volitakes Dr. Guiseppe Ciccotosto Jeffrey Kwok Nicole Critch Nikki Sherratt Mikhalina Cortes Varsha Lal Prof. Colin L. Masters Kazuma Murakami Prof. Roberto Cappai Dr. Paul A. Adlard Prof. Kevin J. Barnham 《Angewandte Chemie (International ed. in English)》2013,52(12):3374-3378
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Rational Design and Identification of a Non‐Peptidic Aggregation Inhibitor of Amyloid‐β Based on a Pharmacophore Motif Obtained from cyclo[‐Lys‐Leu‐Val‐Phe‐Phe‐] 下载免费PDF全文
Tadamasa Arai Takushi Araya Dr. Daisuke Sasaki Dr. Atsuhiko Taniguchi Dr. Takeshi Sato Dr. Youhei Sohma Prof. Motomu Kanai 《Angewandte Chemie (International ed. in English)》2014,53(31):8236-8239
Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small‐molecule aggregation inhibitors of Alzheimer’s amyloid‐β (Aβ) are extremely scarce, however, and are mainly restricted to dye‐ and polyphenol‐type compounds that lack drug‐likeness. Based on the structure‐activity relationship of cyclic Aβ16–20 (cyclo‐[KLVFF]), we identified unique pharmacophore motifs comprising side‐chains of Leu2, Val3, Phe4, and Phe5 residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non‐peptidic, small‐molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non‐peptidic, small‐molecule aggregation inhibitors of amyloids based on rational molecular design. 相似文献