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1.
Hydrophobic collapse plays crucial roles in protein functions, from accessing the complex three‐dimensional structures of native enzymes to the dynamic polymerization of non‐equilibrium microtubules. However, hydrophobic collapse can also lead to the thermodynamically downhill aggregation of aberrant proteins, which has interestingly led to the development of a unique class of soft nanomaterials. There remain critical gaps in the understanding of the mechanisms of how hydrophobic collapse can regulate such aggregation. Demonstrated herein is a methodology for non‐equilibrium amyloid polymerization through mutations of the core sequence of Aβ peptides by a thermodynamically activated moiety. An out of equilibrium state is realized because of the negative feedback from the transiently formed cross‐β amyloid networks. Such non‐equilibrium amyloid nanostructures were utilized to access temporal control over its electronic properties.  相似文献   

2.
Targeting amyloid‐β (Aβ)‐induced complex neurotoxicity has received considerable attention in the therapeutic and preventive treatment of Alzheimer’s disease (AD). The complex pathogenesis of AD suggests that it requires comprehensive treatment, and drugs with multiple functions against AD are more desirable. Herein, AuNPs@POMD‐pep (AuNPs: gold nanoparticles, POMD: polyoxometalate with Wells–Dawson structure, pep: peptide) were designed as a novel multifunctional Aβ inhibitor. AuNPs@POMD‐pep shows synergistic effects in inhibiting Aβ aggregation, dissociating Aβ fibrils and decreasing Aβ‐mediated peroxidase activity and Aβ‐induced cytotoxicity. By taking advantage of AuNPs as vehicles that can cross the blood–brain barrier (BBB), AuNPs@POMD‐pep can cross the BBB and thus overcome the drawbacks of small‐molecule anti‐AD drugs. Thus, this work provides new insights into the design and synthesis of inorganic nanoparticles as multifunctional therapeutic agents for treatment of AD.  相似文献   

3.
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   

4.
Herein, to mimic complex natural system, polyelectrolyte multilayer (PEM)‐coated mesoporous silica nanoreactors were used to compartmentalize two different artificial enzymes. PEMs coated on the surface of mesoporous silica could serve as a permeable membrane to control the flow of molecules. When assembling hemin on the surface of mesoporous silica, the hemin‐based mesoporous silica system possessed remarkable peroxidase‐like activity, especially at physiological pH, and could be recycled more easily than traditional graphene–hemin nanocompounds. The hope is that these new findings may pave the way for exploring novel nanoreactors to achieve compartmentalization of nanozymes and applying artificial cascade catalytic systems to mimic cell organelles or important biochemical transformations  相似文献   

5.
Alzheimer's disease (AD) is a neurodegenerative disorder and the primary cause of age‐related dementia. The etiology of AD is complex and has not been completely elucidated. Herein, we report that treatment with elastin‐like polypeptides (ELPs), a component of the brain extracellular matrix (ECM), significantly increased the levels of AD‐related amyloid‐β peptides (Aβ) both in vitro and in vivo. Regarding the molecular mechanism(s), the upregulation of Aβ levels was related to increased proteolytic processing of the amyloid precursor protein. Furthermore, nesting tests demonstrated that the ELP‐treated animals showed significant neurobehavioral deficits with cognitive impairment. These results suggest that the elastin is associated with AD‐related pathological and behavioral changes. This finding presents a new aspect for Alzheimer's amyloidosis event and provides a great promise in developing ELP‐based model systems to better understand the pathogenesis of AD.  相似文献   

6.
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   

7.
A small library of rationally designed amyloid β [Aβ(1–40)] peptide variants is generated, and the morphology of their fibrils is studied. In these molecules, the structurally important hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) is systematically mutated to introduce defined physical forces to act as specific internal constraints on amyloid formation. This Aβ(1–40) peptide library is used to study the fibril morphology of these variants by employing a comprehensive set of biophysical techniques including solution and solid‐state NMR spectroscopy, AFM, fluorescence correlation spectroscopy, and XRD. Overall, the findings demonstrate that the introduction of significant local physical perturbations of a crucial early folding contact of Aβ(1–40) only results in minor alterations of the fibrillar morphology. The thermodynamically stable structure of mature Aβ fibrils proves to be relatively robust against the introduction of significantly altered molecular interaction patterns due to point mutations. This underlines that amyloid fibril formation is a highly generic process in protein misfolding that results in the formation of the thermodynamically most stable cross‐β structure.  相似文献   

8.
Two methods are reported for the 1,2‐ and 1,1‐arylboration of α‐methyl vinyl arenes. In the case of 1,2‐arylboration, the formation of a quaternary center occurred through a rare cross‐coupling reaction of a tertiary organometallic complex. 1,1‐Arylboration was enabled by catalyst optimization and occurred through a β‐hydride elimination/reinsertion cascade. Enantioselective variants of both processes are presented as well as mechanistic investigations.  相似文献   

9.
A series of doubly β‐to‐β bridged cyclic ZnII porphyrin arrays were prepared by a stepwise Suzuki–Miyaura coupling reaction of borylated ZnII porphyrin with different bridge groups. The coupling of the building block of β,β′‐diboryl ZnII porphyrin 1 with different bridges provided the doubly β‐to‐β carbazole‐bridged ZnII porphyrin array 3 , the fluorene‐bridged ZnII porphyrin array 5 , the fluorenone‐bridged ZnII porphyrin array 7 , and the three‐carbazole‐bridged ZnII porphyrin ring 8 . The structural assignment of 3 was confirmed by the X‐ray diffraction analysis, which revealed a highly symmetrical and remarkably bent syn‐form structure. The incorporation of bridge units with different electronic effects results in different photophysical properties of the cyclic ZnII porphyrin arrays. Comprehensive photophysical studies demonstrate that the electron‐withdrawing bridge fluorenone has the largest electronic interaction with the ZnII porphyrin unit among the series, thus resulting in the highest two‐photon absorption cross‐section values (σ(2)) of 6570±60 GM for 7 . The present work provides a new strategy for developing porphyrin‐based optical materials.  相似文献   

10.
A wealth of epidemiological evidence indicates a strong link between type 2 diabetes (T2D) and Alzheimer's disease (AD). The fiber deposition with cross‐β‐sheet structure formed by self‐aggregation and misfolding of amyloidogenic peptides is a common hallmark of both diseases. For the patients with T2D, the fibrils are mainly found in the islets of Langerhans that results from the accumulation of human islet amyloid polypeptide (hIAPP). The major component of aggregates located in the brain of AD patients is amyloid‐β (Aβ). Many biophysical and physiological properties are shared by hIAPP and Aβ, and both peptides show similar cytotoxic mechanisms. Therefore, it is meaningful to investigate the possible cross‐interactions of hIAPP and Aβ in both diseases. In this article, the segment 25–35 of Aβ was selected because Aβ25–35 was a core region in the process of amyloid formation and showed similar aggregation tendency and toxicity with full‐length Aβ. The electrospray ionization‐ion mobility‐mass spectrometry analysis and thioflavin T fluorescence kinetic analysis combined with transmission electron microscopy were used to explore the effects of the coexistence of Aβ25–35 and hIAPP on the self‐aggregation of both peptides and whether there was co‐assembly in fibrillation. The results indicated that the aggregation of hIAPP and Aβ25–35 had two nucleation stages in the binary mixtures. hIAPP and Aβ25–35 had a high binding affinity and a series of hetero‐oligomers formed in the mixtures of hIAPP and Aβ25–35 in the early stage. The cross‐reaction between hIAPP monomers and Aβ25–35 monomers as well as a little of oligomers during primary nucleation stage could accelerate the aggregation of Aβ25–35. However, owing to the obvious difference in aggregation ability between hIAPP and Aβ25–35, this cross‐interaction had no significant impact on the self‐assembly of hIAPP. Our study may offer a better understanding for exploring the molecular mechanism of the association between AD and T2D observed in clinical and epidemiological studies and developing therapeutic strategies against amyloid diseases.  相似文献   

11.
In Alzheimer’s disease, amyloid‐β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β‐sheet conformation, binds to the Aβ peptide hairpin‐stacked fibril through β‐sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four‐times higher than that of the natural product was identified.  相似文献   

12.
The self‐assembly of short peptides gives rise to versatile nanoassemblies capable of promoting efficient catalysis. We have semi‐rationally designed a series of seven‐residue peptides that form hemin‐binding catalytic amyloids to facilitate enantioselective cyclopropanation with efficiencies that rival those of engineered hemin proteins. These results demonstrate that: 1) Catalytic amyloids can bind complex metallocofactors to promote practically important multisubstrate transformations. 2) Even essentially flat surfaces of amyloid assemblies can impart a substantial degree of enantioselectivity without the need for extensive optimization. 3) The ease of peptide preparation allows for straightforward incorporation of unnatural amino acids and the preparation of peptides made from d ‐amino acids with complete reversal of enantioselectivity.  相似文献   

13.
The aggregation of amyloid‐β peptide and its accumulation in the human brain has an important role in the etiology of Alzheimer’s disease. Thioflavin T has been widely used as a fluorescent marker for these amyloid aggregates. Nevertheless, its complex photophysical behavior, with strong wavelength dependencies of all its fluorescence properties, requires searching for new fluorescent probes. The use of 2‐(2′‐hydroxyphenyl)imidazo[4,5‐b]pyridine (HPIP), which shows two emission bands and a rich excited‐state behavior due to the existence of excited‐state intramolecular processes of proton transfer and charge transfer, is proposed. These properties result in a high sensitivity of HPIP fluorescence to its microenvironment and cause a large differential fluorescence enhancement of the two bands upon binding to aggregates of the amyloid‐β peptide. Based on this behavior, a very sensitive ratiometric method is established for the detection and quantification of amyloid fibrils, which can be combined with the monitoring of fluorescence anisotropy. The binding selectivity of HPIP is discussed on the basis of the apparent binding equilibrium constants of this probe to amyloid‐β (1–42) fibrils and to the nonfibrillar protein bovine serum albumin. Finally, an exhaustive comparison between HPIP and thioflavin T is presented to discuss the sensitivity and specificity of these probes to amyloid aggregates and the significant advantages of the HPIP dye for quantitative determinations.  相似文献   

14.
The novel tricyclic spiroketal alotane‐type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)‐alotaketals A–D and (−)‐phorbaketal A were accomplished [29–31 steps from (−)‐malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ‐keto‐alcohols to forge the common tricyclic spiroketal intermediate, 2) a late‐stage allylic C−H oxidation, and 3) olefin cross‐metathesis to install the different side chains.  相似文献   

15.
Amyloid fibrils are filamentous and insoluble forms of peptides or proteins. Proline has long been considered to be incompatible with the cross‐β structural motif of amyloid fibrils. On the basis of solid‐state NMR spectroscopy data, we present a structural model of an in‐register parallel β sheet for the amyloid fibrils formed from a human prion protein fragment, huPrP127–47. We have developed a simple solid‐state NMR spectroscopy technique to identify solvent‐protected backbone amide protons in a H/D exchange experiment without disaggregating the amyloid fibrils, from which we find that proline residue P137 does not disrupt the β‐sheet structure from G127 to G142. We suggest that the resultant kink at P137 generates a twist between adjacent peptide strands to maintain hydrogen bonding in the β‐sheet regions flanking the P137 residue. Although proline can be well integrated into the cross‐β structure of amyloid fibrils, the kink formed at the position of the proline residue will considerably weaken the hydrogen bonding between the neighboring strands, especially when the mutation site is near the central region of a β sheet.  相似文献   

16.
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   

17.
In addition to the prototypic amyloid‐β (Aβ) peptides Aβ1–40 and Aβ1–42, several Aβ variants differing in their amino and carboxy termini have been described. Synthetic availability of an Aβ variant is often the key to study its role under physiological or pathological conditions. Herein, we report a protocol for the efficient solid‐phase peptide synthesis of the N‐terminally elongated Aβ‐peptides Aβ?3–38, Aβ?3–40, and Aβ?3–42. Biophysical characterization by NMR spectroscopy, CD spectroscopy, an aggregation assay, and electron microscopy revealed that all three peptides were prone to aggregation into amyloid fibrils. Immunoprecipitation, followed by mass spectrometry, indicated that Aβ?3–38 and Aβ?3–40 are generated by transfected cells even in the presence of a tripartite β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. The elongated Aβ peptides starting at Val(?3) can be separated from N‐terminally‐truncated Aβ forms by high‐resolution isoelectric‐focusing techniques, despite virtually identical isoelectric points. The synthetic Aβ variants and the methods presented here are providing tools to advance our understanding of the potential roles of N‐terminally elongated Aβ variants in Alzheimer's disease.  相似文献   

18.
The title compound, C16H30N2O5, crystallizes with three molecules in the asymmetric unit, each adopting a β‐strand/polyproline II backbone conformation. The main‐chain functional groups are hydrogen bonded into tapes having the characteristics of parallel β‐sheets. Each tape has a left‐handed twist and thus forms a helix, with six peptide molecules needed to complete a full 360° rotation. A comparison of hydrogen‐bond lengths and twisting modes is made with other related structures of protected dipeptides and with a hexapeptide derived from amyloid‐β containing the Val–Val segment. Additionally, a comparison of the backbone conformation is made with that of the Val141–Val142 segment of the water channel aquaporin‐4 (AQP4).  相似文献   

19.
Transmissible spongiform encephalopathy is associated with misfolding of prion protein (PrP) into an amyloid β‐rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer′s disease amyloid‐β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP‐amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP. This unanticipated nonspecific amyloidogenic effect of Aβ indicates that this peptide might be involved in widespread protein aggregation, regardless of the amino acid sequences of target proteins, and exacerbate the pathology of many neurodegenerative diseases.  相似文献   

20.
Brain copper imbalance plays an important role in amyloid‐β aggregation, tau hyperphosphorylation, and neurotoxicity observed in Alzheimer's disease (AD). Therefore, the administration of biocompatible metal‐binding agents may offer a potential therapeutic solution to target mislocalized copper ions and restore metallostasis. Histidine‐containing peptides and proteins are excellent metal binders and are found in many natural systems. The design of short peptides showing optimal binding properties represents a promising approach to capture and redistribute mislocalized metal ions, mainly due to their biocompatibility, ease of synthesis, and the possibility of fine‐tuning their metal‐binding affinities in order to suppress unwanted competitive binding with copper‐containing proteins. In the present study, three peptides, namely HWH , HKCH , and HAH , have been designed with the objective of reducing copper toxicity in AD. These tripeptides form highly stable albumin‐like complexes, showing higher affinity for CuII than that of Aβ(1‐40). Furthermore, HWH , HKCH , and HAH act as very efficient inhibitors of copper‐mediated reactive oxygen species (ROS) generation and prevent the copper‐induced overproduction of toxic oligomers in the initial steps of amyloid aggregation in the presence of CuII ions. These tripeptides, and more generally small peptides including the sequence His‐Xaa‐His at the N‐terminus, may therefore be considered as promising motifs for the future development of new and efficient anti‐Alzheimer drugs.  相似文献   

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