共查询到20条相似文献,搜索用时 15 毫秒
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Zheng Niu Elke Prade Eleni Malideli Kathleen Hille Alexander Jussupow Yonatan G. Mideksa Li‐Mei Yan Chen Qian Markus Fleisch Ana C. Messias Riddhiman Sarkar Michael Sattler Don C. Lamb Matthias J. Feige Carlo Camilloni Aphrodite Kapurniotu Bernd Reif 《Angewandte Chemie (International ed. in English)》2020,59(14):5771-5781
Designed peptides derived from the islet amyloid polypeptide (IAPP) cross‐amyloid interaction surface with Aβ (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of Aβ amyloid self‐assembly. However, the molecular mechanism of their function is not well understood. Using solution‐state and solid‐state NMR spectroscopy in combination with ensemble‐averaged dynamics simulations and other biophysical methods including TEM, fluorescence spectroscopy and microscopy, and DLS, we characterize ISM structural preferences and interactions. We find that the ISM peptide R3‐GI is highly dynamic, can adopt a β‐like structure, and oligomerizes into colloid‐like assemblies in a process that is reminiscent of liquid–liquid phase separation (LLPS). Our results suggest that such assemblies yield multivalent surfaces for interactions with Aβ40. Sequestration of substrates into these colloid‐like structures provides a mechanistic basis for ISM function and the design of novel potent anti‐amyloid molecules. 相似文献
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Inhibition of Amyloid Fibril Growth and Dissolution of Amyloid Fibrils by Curcumin–Gold Nanoparticles 下载免费PDF全文
Sharbari Palmal Amit Ranjan Maity Brijesh Kumar Singh Sreetama Basu Prof. Nihar R. Jana Dr. Nikhil R. Jana 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(20):6184-6191
Inhibition of amyloid fibrillation and clearance of amyloid fibrils/plaques are essential for the prevention and treatment of various neurodegenerative disorders involving protein aggregation. Herein, we report curcumin‐functionalized gold nanoparticles (Au‐curcumin) of hydrodynamic diameter 10–25 nm, which serve to inhibit amyloid fibrillation and disintegrate/dissolve amyloid fibrils. In nanoparticle form, curcumin is water‐soluble and can efficiently interact with amyloid protein/peptide, offering enhanced performance in inhibiting amyloid fibrillation and dissolving amyloid fibrils. Our results imply that nanoparticle‐based artificial molecular chaperones may offer a promising therapeutic approach to combat neurodegenerative disease. 相似文献
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Jakob T. Nielsen Dr. Morten Bjerring Dr. Martin D. Jeppesen Ronnie O. Pedersen Jan M. Pedersen Dr. Kim L. Hein Thomas Vosegaard Dr. Troels Skrydstrup Prof. Daniel E. Otzen Prof. Niels C. Nielsen Prof. 《Angewandte Chemie (International ed. in English)》2009,48(12):2118-2121
The fibril structure formed by the amyloidogenic fragment SNNFGAILSS of the human islet amyloid polypeptide (hIAPP) is determined with 0.52 Å resolution. Symmetry information contained in the easily obtainable resonance assignments from solid‐state NMR spectra (see picture), along with long‐range constraints, can be applied to uniquely identify the supramolecular organization of fibrils.
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Dr. Volodymyr V. Shvadchak Kseniia Afitska Dr. Dmytro A. Yushchenko 《Angewandte Chemie (International ed. in English)》2018,57(20):5690-5694
Misfolding of the protein α‐synuclein (αSyn) into amyloid fibrils plays a central role in the development of Parkinson's disease. Most approaches for the inhibition of αSyn fibril formation are based on stabilizing the native monomeric form of the protein or destabilizing the fibrillized misfolded form. They require high concentrations of inhibitor and therefore cannot be easily used for therapies. In this work, we designed an inhibitor (Inh‐β) that selectively binds the growing ends of αSyn fibrils and creates steric hindrance for the binding of monomeric αSyn. This approach permits the inhibition of fibril formation at Inh‐β concentrations (IC50=850 nm ) much lower than the concentration of monomeric αSyn. We studied its kinetic mechanism in vitro and identified the reactions that limit inhibition efficiency. It is shown that blocking of αSyn fibril ends is an effective approach to inhibiting fibril growth and provides insights for the development of effective inhibitors of αSyn aggregation. 相似文献
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Tingting Chen Gang Wang Lin Tang Hongpeng Yang Jing Xu Xiaoxue Wen Yunbo Sun Shuchen Liu Tao Peng Shouguo Zhang Lin Wang 《Molecules (Basel, Switzerland)》2022,27(7)
Significant efforts have been made in recent years to identify more environmentally benign and safe alternatives to side-chain protection and deprotection in solid-phase peptide synthesis (SPPS). Several protecting groups have been endorsed as suitable candidates, but finding a greener protecting group in SPPS has been challenging. Here, based on the 2-(o-nitrophenyl) propan-1-ol (Npp-OH) photolabile protecting group, a structural modification was carried out to synthesize a series of derivatives. Through experimental verification, we found that 3-(o-Nitrophenyl) butan-2-ol (Npb-OH) had a high photo-release rate, high tolerance to the key conditions of Fmoc-SPPS (20% piperidine DMF alkaline solution, and pure TFA acidic solution), and applicability as a carboxyl-protective group in aliphatic and aromatic carboxyl groups. Finally, Npb-OH was successfully applied to the synthesis of head–tail cyclic peptides and side-chain–tail cyclic peptides. Moreover, we found that Npb-OH could effectively resist diketopiperazines (DKP). The α-H of Npb-OH was found to be necessary for its photosensitivity in comparison to 3-(o-Nitrophenyl)but-3-en-2-ol (Npbe-OH) during photolysis-rate verification. 相似文献
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Dr. Timothy A. Hill Dr. Nicholas E. Shepherd Dr. Frederik Diness Prof. Dr. David P. Fairlie 《Angewandte Chemie (International ed. in English)》2014,53(48):13020-13041
Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well‐defined three‐dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein‐like structures in water. However, short peptides can be induced to fold into protein‐like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine‐tune three‐dimensional structure. Such constrained cyclic peptides can have protein‐like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three‐dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties. 相似文献
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The mechanism for the interaction of thioflavin T (ThT) with amyloid fibrils at the molecular level is not known. Here, we used 1H NMR spectroscopy to determine the binding mode of ThT on the surface of fibrils from lysozyme and insulin. Relayed rotating‐frame Overhauser enhancements in ThT were observed, indicating that the orientation of ThT is orthogonal to the fibril surface. Importantly, the assembly state of ThT on both surfaces is different. On the surface of insulin fibrils, ThT is oligomeric, as indicated by rapid 1H spin‐lattice relaxation rate in the rotating frame (R1ρ), presumably due to intermolecular dipole–dipole interactions between ThT molecules. In contrast, ThT on the surface of lysozyme fibrils is a monomer, as indicated by slower 1H R1ρ. These results shed new light into the mechanism for the enhancement of ThT fluorescence and may lead to more efficient detectors of amyloid assemblies, which have escaped detection by ThT in monomer form. 相似文献
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Jehad Almaliti Muhammed Alzweiri Momen Alhindy Tamam Al-Helo Ibrahim Daoud Raghad Deknash C. Benjamin Naman Bashaer Abu-Irmaileh Yasser Bustanji Islam Hamad 《Molecules (Basel, Switzerland)》2022,27(7)
Obesity is the most common nutritional disorder in the developed world and is associated with important comorbidities. Pancreatic lipase (PL) inhibitors play a key role in the metabolism of human fat. A series of novel epoxyketones peptide derivatives were investigated for their pancreatic lipase inhibitory activity. The epoxyketone moiety is a well-known reactive electrophile group that has been used as part of proteasome inhibitors in cancer therapy, and it is widely believed that these are very selective for targeting the proteasome active site. Here we investigated various peptide derivatives with an epoxide warhead for their anti-lipase activity. The assessment of these novel epoxyketones was performed by an in-house method that we developed for rapid screening and identification of lipase inhibitors using GC-FID. Herein, we present a novel anti-lipase pharmacophore based on epoxyketone peptide derivatives that showed potent anti-lipase activity. Many of these derivatives had comparable or more potent activity than the clinically used lipase inhibitors such as orlistat. In addition, the lipase appears to be inhibited by a wide range of epoxyketone analogues regardless of the configuration of the epoxide in the epoxyketone moiety. The presented data in this study shows the first example of the use of epoxyketone peptides as novel lipase inhibitors. 相似文献
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Dr. Andrew M. White Dr. Simon J. de Veer Guojie Wu Dr. Peta J. Harvey Kuok Yap Dr. Gordon J. King Dr. Joakim E. Swedberg Dr. Conan K. Wang Dr. Ruby H. P. Law Dr. Thomas Durek Prof. David J. Craik 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(28):11369-11373
Ruthenium-catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5-disubstituted 1,2,3-triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross-linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor-1. NMR and X-ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole-bridged peptides also displayed superior half-lives in liver S9 stability assays compared to disulfide-bridged peptides. This work establishes a foundation for the application of 1,5-disubstituted 1,2,3-triazoles as disulfide mimetics. 相似文献
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A Hot‐Segment‐Based Approach for the Design of Cross‐Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self‐Assembly 下载免费PDF全文
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
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Dr. Trung Quan Luong Nelli Erwin Matthias Neumann Andreas Schmidt Cornelia Loos Prof. Dr. Volker Schmidt Prof. Dr. Marcus Fändrich Prof. Dr. Roland Winter 《Angewandte Chemie (International ed. in English)》2016,55(40):12412-12416
We studied the combined effects of pressure (0.1–200 MPa) and temperature (22, 30, and 38 °C) on the catalytic activity of designed amyloid fibrils using a high‐pressure stopped‐flow system with rapid UV/Vis absorption detection. Complementary FT‐IR spectroscopic data revealed a remarkably high pressure and temperature stability of the fibrillar systems. High pressure enhances the esterase activity as a consequence of a negative activation volume at all temperatures (about ?14 cm3 mol?1). The enhancement is sustained in the whole temperature range covered, which allows a further acceleration of the enzymatic activity at high temperatures (activation energy 45–60 kJ mol?1). Our data reveal the great potential of using both pressure and temperature modulation to optimize the enzyme efficiency of catalytic amyloid fibrils. 相似文献
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Dr. Wael E. Houssen Andrew F. Bent Dr. Andrew R. McEwan Nathalie Pieiller Dr. Jioji Tabudravu Dr. Jesko Koehnke Greg Mann Rosemary I. Adaba Dr. Louise Thomas Dr. Usama W. Hawas Dr. Huanting Liu Dr. Ulrich Schwarz‐Linek Prof. Margaret C. M. Smith Prof. James H. Naismith Prof. Marcel Jaspars 《Angewandte Chemie (International ed. in English)》2014,53(51):14171-14174
Heterocycle‐containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine‐derived enzymes and substrates obtained from a family of ribosomally produced and post‐translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non‐native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6–9 residues representing 11 out of the 20 canonical amino acids. 相似文献
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Functional amyloids belong to an increasing class of non-toxic biologic material, in contrast to the prominent disease-related amyloids. Herein, this work reports on the fibril formation of the parathyroid hormone PTH84 as a representative candidate following the same generic principles of primary and secondary nucleation. Employing Thioflavin T monitored kinetics analyses and negative-staining transmission electron microscopy, an intricate, concentration dependent behavior of time dependent generation and morphologies of PTH84 fibrils are found. While at low peptide concentrations, fibril formation is driven by surface catalyzed secondary nucleation, an increased amount of peptides cause a negative feedback on fibril elongation and secondary nucleation. Moreover, the source of primary nuclei is found to regulate the overall macroscopic fibrillation. As a consequence, the concentration dependent competition of primary versus secondary nucleation pathways is found to dominate the mechanism of fibril generation. This work is able to hypothesize an underlying monomer-oligomer equilibrium providing high-order species for primary nucleation and, additionally, negatively affecting the available monomer pool. 相似文献
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Sushma Subedi Santanu Sasidharan Niharika Nag Prakash Saudagar Timir Tripathi 《Molecules (Basel, Switzerland)》2022,27(6)
Most neurodegenerative diseases such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, etc. are caused by inclusions and plaques containing misfolded protein aggregates. These protein aggregates are essentially formed by the interactions of either the same (homologous) or different (heterologous) sequences. Several experimental pieces of evidence have revealed the presence of cross-seeding in amyloid proteins, which results in a multicomponent assembly; however, the molecular and structural details remain less explored. Here, we discuss the amyloid proteins and the cross-seeding phenomena in detail. Data suggest that targeting the common epitope of the interacting amyloid proteins may be a better therapeutic option than targeting only one species. We also examine the dual inhibitors that target the amyloid proteins participating in the cross-seeding events. The future scopes and major challenges in understanding the mechanism and developing therapeutics are also considered. Detailed knowledge of the amyloid cross-seeding will stimulate further research in the practical aspects and better designing anti-amyloid therapeutics. 相似文献