共查询到20条相似文献,搜索用时 15 毫秒
1.
Dr. Hamed Shaykhalishahi Dr. Aziz Gauhar Michael M. Wördehoff Dr. Clara S. R. Grüning Antonia N. Klein Dr. Oliver Bannach Dr. Matthias Stoldt Prof. Dr. Dieter Willbold Prof. Dr. Torleif Härd Dr. Wolfgang Hoyer 《Angewandte Chemie (International ed. in English)》2015,54(30):8837-8840
Conversion of the intrinsically disordered protein α‐synuclein (α‐syn) into amyloid aggregates is a key process in Parkinson’s disease. The sequence region 35–59 contains β‐strand segments β1 and β2 of α‐syn amyloid fibril models and most disease‐related mutations. β1 and β2 frequently engage in transient interactions in monomeric α‐syn. The consequences of β1–β2 contacts are evaluated by disulfide engineering, biophysical techniques, and cell viability assays. The double‐cysteine mutant α‐synCC, with a disulfide linking β1 and β2, is aggregation‐incompetent and inhibits aggregation and toxicity of wild‐type α‐syn. We show that α‐syn delays the aggregation of amyloid‐β peptide and islet amyloid polypeptide involved in Alzheimer’s disease and type 2 diabetes, an effect enhanced in the α‐synCC mutant. Tertiary interactions in the β1–β2 region of α‐syn interfere with the nucleation of amyloid formation, suggesting promotion of such interactions as a potential therapeutic approach. 相似文献
2.
Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies 下载免费PDF全文
Dr. Marina Chemerovski‐Glikman Eva Rozentur‐Shkop Dr. Michal Richman Dr. Asaf Grupi Asaf Getler Prof. Haim Y. Cohen Dr. Hadassa Shaked Cecilia Wallin Dr. Sebastian K. T. S. Wärmländer Prof. Elisha Haas Prof. Astrid Gräslund Prof. Jordan H. Chill Prof. Shai Rahimipour 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(40):14236-14246
Many peptides and proteins with large sequences and structural differences self‐assemble into disease‐causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross‐interaction. Here, we demonstrate how the self‐assembled, cyclic d,l ‐α‐peptide CP‐2 , which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson′s disease associated α‐synuclein (α‐syn) aggregation to toxic oligomers by an ?off‐pathway“ mechanism. We show that CP‐2 interacts with the N‐terminal and the non‐amyloid‐β component region of α‐syn, which are responsible for α‐syn′s membrane intercalation and self‐assembly, thus changing the overall conformation of α‐syn. CP‐2 also remodels α‐syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular α‐syn in neuronal cells overexpressing α‐syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases. 相似文献
3.
Influence of the β‐Sheet Content on the Mechanical Properties of Aggregates during Amyloid Fibrillization 下载免费PDF全文
Jae Sun Jeong Prof. Hilal A. Lashuel Prof. Raffaele Mezzenga Prof. Giovanni Dietler 《Angewandte Chemie (International ed. in English)》2015,54(8):2462-2466
Amyloid fibrils associated with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, consist of insoluble aggregates of α‐synuclein and Aβ‐42 proteins with a high β‐sheet content. The aggregation of both proteins occurs by misfolding of the monomers and proceeds through the formation of intermediate oligomeric and protofibrillar species to give the final fibrillar cross‐β‐sheet structure. The morphological and mechanical properties of oligomers, protofibrils, and fibrils formed during the fibrillization process were investigated by thioflavin T fluorescence and circular dichroism in combination with AFM peak force quantitative nanomechanical technique. The results reveal an increase in the Young’s modulus during the transformation from oligomers to mature fibrils, thus inferring that the difference in their mechanical properties is due to an internal structural change from a random coil to a structure with increased β‐sheet content. 相似文献
4.
Charge‐Induced Secondary Structure Transformation of Amyloid‐Derived Dipeptide Assemblies from β‐Sheet to α‐Helix 下载免费PDF全文
Dr. Ruirui Xing Dr. Chengqian Yuan Dr. Shukun Li Dr. Jingwen Song Prof. Dr. Junbai Li Prof. Xuehai Yan 《Angewandte Chemie (International ed. in English)》2018,57(6):1537-1542
Secondary structures such as α‐helix and β‐sheet are the major structural motifs within the three‐dimensional geometry of proteins. Therefore, structure transitions from β‐sheet to α‐helix not only can serve as an effective strategy for the therapy of neurological diseases through the inhibition of β‐sheet aggregation but also extend the application of α‐helix fibrils in biomedicine. Herein, we present a charge‐induced secondary structure transition of amyloid‐derived dipeptide assemblies from β‐sheet to α‐helix. We unravel that the electrostatic (charge) repulsion between the C‐terminal charges of the dipeptide molecules are responsible for the conversion of the secondary structure. This finding provides a new perspective to understanding the secondary structure formation and transformation in the supramolecular organization and life activity. 相似文献
5.
Yuko Murakoshi Dr. Tsuyoshi Takahashi Prof. Dr. Hisakazu Mihara 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(14):4525-4531
Aggregation of amyloid β‐peptide (Aβ) is closely related to the pathogenesis of Alzheimer’s disease (AD). Although much effort has been devoted to the construction of molecules that inhibit the aggregation of Aβ1‐42, high doses are needed for the inhibition of Aβ aggregation in many cases. Previously, we reported that designed green fluorescent protein (GFP) analogues that gives pseudo‐Aβ β‐sheet structures can work as an aggregation inhibitor against Aβ. To further test this design strategy, we constructed protein analogues that mimic Aβ β‐sheet structures of amyloids by using insulin‐like growth factor 2 receptor domain 11 (IGF2R‐d11) as a scaffold. A designed protein, named IG11KK, which has a parallel configuration of Aβ‐like β sheets, can bind more preferentially to oligomeric Aβ1‐42 than the monomer. Moreover, IG11KK suppressed the aggregation of Aβ1‐42 efficiently, even though lower concentrations of IG11KK than Aβ were used. The aggregation kinetics of Aβ in the presence of the designed proteins revealed that IG11KK can work as an inhibitor not only for the early to middle stages, but also in the latter stage of Aβ aggregation owing to its favorable binding to oligomeric structures of Aβ. The design strategy using β‐barrel proteins such as IGF2R‐d11 and GFP is useful in generating excellent inhibitors of protein misfolding and amyloid formation. 相似文献
6.
Ya‐Kun Li Ming‐Wei Jiang Liang Wang Cheng‐Gong Guo Youqian Xu Cai‐Qi Wang 《Journal of Polymer Science.Polymer Physics》2013,51(22):1598-1606
In general, the complexation and gelation behavior between biocompatible poly(ε‐caprolactone) (PCL) derivatives and α‐cyclodextrin (α‐CD) is extensively studied in water, but not in organic solvents. In this article, the complexation and gelation behavior between α‐CD and multi‐arm polymer β‐cyclodextrin‐PCL (β‐CD‐PCL) with a unique “jellyfish‐like” structure are thoroughly investigated in organic solvent N,N‐dimethylformamide and a new heat‐induced organogel is obtained. However, PCL linear polymers cannot form organogels under the same condition. The complexation is characterized by rheological measurements, DSC, XRD, and SEM. The SEM images reveal that the complexes between β‐CD‐PCL and α‐CD present a novel topological helix porous structure which is distinctly different from the lamellar structure formed by PCL linear polymers and α‐CD, suggesting the unique “jellyfish‐like” structure of β‐CD‐PCL is crucial for the formation of the organogels. This research may provide insight into constructing new supramolecular organogels and potential for designing new functional biomaterials. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013 , 51, 1598–1606 相似文献
7.
Catalytic Asymmetric 1,2‐Addition of α‐Isothiocyanato Phosphonates: Synthesis of Chiral β‐Hydroxy‐ or β‐Amino‐Substituted α‐Amino Phosphonic Acid Derivatives 下载免费PDF全文
Yi‐Ming Cao Fang‐Fang Shen Fu‐Ting Zhang Jin‐Long Zhang Prof. Dr. Rui Wang 《Angewandte Chemie (International ed. in English)》2014,53(7):1862-1866
α‐Amino phosphonic acid derivatives are considered to be the most important structural analogues of α‐amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2‐addition reactions of α‐isothiocyanato phosphonate were developed. Through these processes, derivatives of β‐hydroxy‐α‐amino phosphonic acid and α,β‐diamino phosphonic acid, as well as highly functionalized phosphonate‐substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. >20:1, and >99 % ee). This novel method provides a new route for the enantioselective functionalization of α‐phosphonic acid derivatives. 相似文献
8.
Gangbing Zhu Pengbo Gai Liang Wu Jianhui Zhang Xiaohua Zhang Prof. Dr. Jinhua Chen 《化学:亚洲杂志》2012,7(4):732-737
Naphthol isomers, including α‐naphthol (α‐NAP) and β‐naphthol (β‐NAP), are used widely in various fields and are harmful to the environment and human health. The qualitative and quantitative determination of naphthol isomers is therefore of great significance. Herein, β‐cyclodextrin (β‐CD)‐platinum nanoparticles (Pt NPs)/graphene nanosheets (GNs) nanohybrids (β‐CD‐PtNPs/GNs) were prepared for the first time using a simple wet chemical method and characterized by atomic force microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, and electrochemical methods, and then applied successfully in the ultrasensitive electrochemical detection of naphthol isomers. The results show that the oxidation peak currents of naphthol isomers obtained at the glassy carbon (GC) electrode modified with β‐CD‐PtNPs/GNs are much higher than those at the β‐CD/GNs/GC, PtNPs/GNs/GC, GNs/GC, and bare GC electrodes. Additionally, compared with other electrochemical sensors developed previously, the proposed electrode results in improved detection limits of about one order of magnitude for α‐NAP (0.23 nM ) and three orders of magnitude for β ‐NAP (0.37 nM ). 相似文献
9.
Saayak Halder Narendra Nath Jha Soumik Ray Surabhi Mehra Vipin Agarwal Samir K. Maji 《Angewandte Chemie (International ed. in English)》2018,57(19):5262-5266
α‐Synuclein (α‐Syn) aggregation is associated with Parkinson's disease (PD) pathogenesis. In PD, the role of oligomers versus fibrils in neuronal cell death is debatable, but recent studies suggest oligomers are a proximate neurotoxin. Herein, we show that soluble α‐Syn monomers undergo a transformation from a solution to a gel state on incubation at high concentration. Detailed characterization of the gel showed the coexistence of monomers, oligomers, and short fibrils. In vitro, the gel was highly cytotoxic to human neuroblastoma cells. The individual constituents of the gel are short‐lived species but toxic to the cells. They comprise a structurally heterogeneous population of α‐helical and β‐sheet‐rich oligomers and short fibrils with the cross‐β motif. Given the recent evidence of the gel‐like state of the protein associated with neurodegenerative diseases, the gel state of α‐Syn in this study represents a mechanistic and structural model for the in vivo toxicity of α‐Syn in PD. 相似文献
10.
α,α‐Diaryl(dialkyl)prolinol ethers constitute a potent organocatalyst family which has been shown to be very general for a broad range of reactions involving enamine and iminium ion activation or a combination of both. The reactions are characterized by an efficient steric control approach and can lead to a variety of α‐, β‐, γ‐, and α,β‐functionalized carbonyl compounds with excellent stereocontrol. As a full expression of their catalytic activity, these compounds are also excellent promoters of elegant cascade processes and valuable catalysts in water‐compatible systems. 相似文献
11.
Vincent Terrasson Dr. Renata Marcia de Figueiredo Dr. Jean Marc Campagne Prof. Dr. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2010,16(26):7875-7880
An enantioselective cyclopropanation of α‐substituted α,β‐unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/α‐alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the α‐position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and α,β‐unsaturated aldehydes previously reported by other groups. Very good yields (up to 81 %) and enantioselectivities (up to 97 % ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures. 相似文献
12.
Tatsuya Ikenoue Prof. Dr. Young‐Ho Lee Prof. Dr. József Kardos Miyu Saiki Prof. Dr. Hisashi Yagi Prof. Dr. Yasushi Kawata Prof. Dr. Yuji Goto 《Angewandte Chemie (International ed. in English)》2014,53(30):7799-7804
Although amyloid fibrils are associated with numerous pathologies, their conformational stability remains largely unclear. Herein, we probe the thermal stability of various amyloid fibrils. α‐Synuclein fibrils cold‐denatured to monomers at 0–20 °C and heat‐denatured at 60–110 °C. Meanwhile, the fibrils of β2‐microglobulin, Alzheimer’s Aβ1‐40/Aβ1‐42 peptides, and insulin exhibited only heat denaturation, although they showed a decrease in stability at low temperature. A comparison of structural parameters with positive enthalpy and heat capacity changes which showed opposite signs to protein folding suggested that the burial of charged residues in fibril cores contributed to the cold denaturation of α‐synuclein fibrils. We propose that although cold‐denaturation is common to both native proteins and misfolded fibrillar states, the main‐chain dominated amyloid structures may explain amyloid‐specific cold denaturation arising from the unfavorable burial of charged side‐chains in fibril cores. 相似文献
13.
Using a fluorometric method with a detection limit of 5 nmol/L, here it is reported that albeit positive results were got from bovine serum albumin (BSA) and chicken ovalbumin (OVA) as published in literature, no detectable amount of hydrogen peroxide (H2O2) was generated during α-synuclein (α-Syn) aggregation in vitro even in the presence of transition metal ions Cu(Ⅱ) or Fe(Ⅲ). The results suggest that the concentration of H2O2 generated during aggregation of α-Syn in vitro be lower than 5 nmol/L beyond the detection limit of the adopted method and it is far too poor to be responsible for the cytotoxicity of α-Syn aggregates, thus allowing people to extensively elucidate the mechanism underlying neurotoxicifies of the aggregates formed by some amyloidogenic proteins. 相似文献
14.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(8):2091-2095
The catalytic asymmetric synthesis of both α‐substituted and α,α‐disubstituted (quaternary) β‐tetralones through direct α‐functionalization of the corresponding β‐tetralone precursor remains elusive. A designed Brønsted base‐squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α‐monosubstituted β‐tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α‐carbon atom of the β‐tetralone exclusively, but adducts including all‐carbon quaternary centers are also formed in highly diastereo‐ and enantioselective manner. 相似文献
15.
α‐Synuclein (α‐S) protein is expressed in presynaptic terminals in the central nervous system. The aggregation of α‐S is implicated in the pathogenesis of Parkinson’s disease (PD). In this report, the interaction of α‐S with clioquinol (CQ) was investigated in the presence of Cu(II) ions using electrochemistry, as well as Thioflavin T‐based fluorescence and Congo Red‐based UV‐Vis studies. In the presence of CQ, the α‐S aggregation rate was observed to decrease. The preliminary results showed promise in the future development of CQ derivatives as novel small molecule therapeutic agents with potential efficacy targeting α‐S in PD therapy. 相似文献
16.
Copper‐Catalyzed Asymmetric Synthesis of Tertiary α‐Hydroxy Phosphonic Acid Derivatives with In Situ Generated Nitrosocarbonyl Compounds as the Oxygen Source 下载免费PDF全文
Dr. Biplab Maji Prof. Dr. Hisashi Yamamoto 《Angewandte Chemie (International ed. in English)》2014,53(52):14472-14475
α‐Hydroxy phosphonic acids and their derivatives are highly bioactive structural motifs. It is now reported that these compounds can be accessed through the copper‐catalyzed direct α‐oxidation of β‐ketophosphonates using in situ generated nitrosocarbonyl compounds as an electrophilic oxygen source. These reactions proceeded in high yields (up to 95 %) and enantioselectivities (up to >99 % ee) for both cyclic as well as acyclic substrates. This method was also applied for the synthesis of α,β‐dihydroxy phosphonates and β‐amino‐α‐hydroxy phosphonates. 相似文献
17.
Weijie Chen Dr. YoungKu Kang Dr. Richard G. Wilde Prof. Dr. Daniel Seidel 《Angewandte Chemie (International ed. in English)》2014,53(20):5179-5182
In contrast to the continuously growing number of methods that allow for the efficient α‐functionalization of amines, few strategies exist that enable the direct functionalization of amines in the β‐position. A general redox‐neutral strategy is outlined for amine β‐functionalization and α,β‐difunctionalization that utilizes enamines generated in situ. This concept is demonstrated in the context of preparing polycyclic N,O‐acetals from simple 1‐(aminomethyl)‐β‐naphthols and 2‐(aminomethyl)‐phenols. 相似文献
18.
Shimin Le Miao Yu Jie Yan 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(51):18836-18842
The α‐catenin/β‐catenin complex serves as a critical molecular interface involved in cadherin–catenin‐based mechanosensing at the cell–cell adherence junction that plays a critical role in tissue integrity, repair, and embryonic development. This complex is subject to tensile forces due to internal actomyosin contractility and external mechanical micro‐environmental perturbation. However, the mechanical stability of this complex has yet to be quantified. Here, we directly quantified the mechanical stability of the α‐catenin/β‐catenin complex and showed that it has enough mechanical stability to survive for tens to hundreds of seconds within physiological level of forces up to 10 pN. Phosphorylation or phosphotyrosine‐mimetic mutations (Y142E or/and T120E) on β‐catenin shorten the mechanical lifetime of the complex by tens of fold over the same force range. These results provide insights into the regulation of the α‐catenin/β‐catenin complex by phosphorylation. 相似文献
19.
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
20.
The oxidation kinetics of β‐isophorone (β‐IP) using molecular oxygen catalyzed by iron(III) acetylacetonate was investigated in a lab‐scale agitator bubbling reactor. β‐IP was found to give keto‐isophorone (KIP) and 4‐hydroxy‐3,5,5‐trimethyl‐2‐cyclohexen‐1‐one (HIP) along with little isomerization product α‐isophorone (α‐IP). The results show that the oxidation reaction took place in the pseudo–first‐order fast reaction regime. The experiment was conducted under the mass transfer reaction regime as the mass transfer resistances could not be easily eliminated. The intrinsic kinetics was obtained through apparent kinetics. The activation energy of oxidation of β‐IP to KIP is 70.5 ± 4.1 kJ mol–1, and the value of ln AKIP is 33.53 ± 1.22. Meanwhile, the activation energy of oxidation of β‐IP to HIP is 86.4 ± 5.4 kJ mol–1 and the value of ln AHIP is 36.23 ± 1.52, which could provide theoretical basis for industrial design, amplification of reactor, and the optimization of reaction. 相似文献