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1.
J Agric Food Chem ; 67(42): 11769-11777, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31575115

RESUMO

The inhibitory effect of brazilin against α-synuclein (α-syn) fibrillogenesis, disruption effect against mature fibrils, and the following cytotoxicity were examined by systematical biochemical, biophysical, cellular biological, and molecular simulation experiments. It is found that brazilin inhibited α-syn fibrillogenesis and disrupted the performed fibrils with a concentration-dependent manner. Moreover, cellular experimental data showed that brazilin effectively reduced the cytotoxicity induced by α-syn aggregates. Finally, molecular dynamics simulations were performed to explore the interactions between brazilin and α-syn pentamer. It is found that brazilin directly interacts with α-syn pentamer, and the hydrophobic interactions are favorable for brazilin binding with the α-syn pentamer, while the electrostatic part provides adverse effects. Three binding regions were identified to inhibit α-syn fibrillogenesis or disrupt the preformed aggregates. Furthermore, six important residues (i.e., G51, V52, A53, E61, V66, and K80) of α-syn were also identified. We expected that brazilin is an effective agent against α-syn fibrillogenesis and associated cytotoxicity.


Assuntos
Amiloide/química , Benzopiranos/química , Substâncias Protetoras/química , alfa-Sinucleína/química , Motivos de Aminoácidos , Amiloide/metabolismo , Amiloide/toxicidade , Animais , Benzopiranos/metabolismo , Linhagem Celular , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Células PC12 , Agregados Proteicos , Ligação Proteica , Ratos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidade
2.
Chem Pharm Bull (Tokyo) ; 67(9): 959-965, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474736

RESUMO

Fibrillated aggregation of amyloid ß (Aß) peptides is a potential factor causing toxic amyloid deposition in neurodegenerative diseases. A toxic fibril formation of Aß is known to be enhanced on the ganglioside-rich lipid membrane containing some amounts of cholesterol and sphingomyelin. This ganglioside-rich membrane is supposed to provide a hydrophobic environment that promotes the formation of Aß fibrils. Molecular dynamics simulations were carried out to investigate the structure of Aß complex in the hydrophobic solution composed of dioxane and water molecules. The Aß conformation was contrasted to that in the aqueous condition by executing multiple computational trials with the calculation models containing one, four, or six Aß peptides. The conformation was also compared between the calculations with the 42-mer (Aß42) and 40-mer (Aß40) peptides. The simulations for Aß42 demonstrated that Aß peptides had a tendency to stretch out in the hydrophobic environment. In contrast, Aß peptides were closely packed in the aqueous solution, and the motions of Aß peptides were suppressed significantly. The N-terminal polar domains of Aß peptides tended to be positioned at the inside of the Aß complex in the hydrophobic environment, which supported the C-terminal domains in expanding outward for inter-molecular interaction. Since Aß peptides were not tightly packed in the hydrophobic environment, the total surface area of the Aß complex in the hydrophobic solution was larger than that in the aqueous one. The simulation for Aß40 peptides also showed a difference between the hydrophobic and aqueous solutions. The difference was compatible with the results of Aß42 in the structure of the Aß complex, while the C-terminal outward expansion was not so distinct as Aß42 peptides.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Dioxanos/química , Interações Hidrofóbicas e Hidrofílicas , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Água/química
3.
J Chem Phys ; 151(8): 084106, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31470712

RESUMO

A novel data-based machine learning algorithm for predicting amyloid aggregation rates is reported in this paper. Based on a highly nonlinear projection from 16 intrinsic features of a protein and 4 extrinsic features of the environment to the protein aggregation rate, a feedforward fully connected neural network (FCN) with one hidden layer is trained on a dataset composed of 21 different kinds of amyloid proteins and tested on 4 rest proteins. FCN shows a much better performance than traditional algorithms, such as multivariable linear regression and support vector regression, with an average accuracy higher than 90%. Furthermore, by the correlation analysis and the principal component analysis, seven key features, folding energy, HP patterns for helix, sheet and helices cross membrane, pH, ionic strength, and protein concentration, are shown to constitute a minimum feature set for characterizing the amyloid aggregation kinetics.


Assuntos
Amiloide/química , Aprendizado de Máquina , Agregados Proteicos , Cinética , Redes Neurais (Computação)
4.
Phys Chem Chem Phys ; 21(37): 20999-21006, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31528872

RESUMO

A substantial number of diseases leading to loss of neurologic functions such as Morbus Alzheimer, Morbus Parkinson, or Chorea Huntington are related to the fibrillation of particular amyloidogenic peptides. In vitro amyloid fibrillation strongly depends on admixture with other proteins and peptides, lipids, nanoparticles, surfactants and polymers. We investigated amyloid-beta 1-40 peptide (Aß1-40) fibrillation in mixture with thermoresponsive poly(oligo(ethylene glycol)macrylates), in which the polymer's hydrophobicity is tuned by variation of the number of ethylene glycol-units in the side chain (m = 1-9), the end groups (B = butoxy; C = carboxy; D = dodecyl; P = pyridyldisulfide) and the degree of polymerization (n) of the polymers. The polymers were prepared via RAFT-polymerization, obtaining a broad range of molecular masses (Mn = 700 to 14 600 g mol-1 kDa-1, polydispersity indices PDI = 1.10 to 1.25) and tunable cloud point temperatures (Tcp), ranging from 42.4 °C to 80 °C, respectively. Proper combination of hydrophobic end groups with hydrophilic side chains of the polymer allowed to alter the hydrophilicity/hydrophobicity of these polymers, which is shown to enhance Aß1-40 aggregation significantly in case of the endgroup D (with n = 16, 23, 56). We observed that the less hydrophilic polymers (m = 1-2) were able to both decrease and elongate the lag (tlag) and characteristic times (tchar) of Aß1-40 fibril formation in dependence of their end groups, molecular mass and hydrophilicity. On the other hand, highly hydrophilic polymers (m = 3, 5, 9) either decreased, or only marginally influenced the lag and characteristic times of Aß1-40 fibrillation, in all cases forming ß-sheet rich fibrils as observed by TEM and CD-spectroscopy. Our results support that balanced hydrophobic and hydrophilic interactions of a polymer with Aß1-40 is important for inhibiting amyloid-formation pathways.


Assuntos
Peptídeos beta-Amiloides/química , Fragmentos de Peptídeos/química , Polímeros/química , Amiloide/química , Amiloide/ultraestrutura , Peptídeos beta-Amiloides/ultraestrutura , Interações Hidrofóbicas e Hidrofílicas , Fragmentos de Peptídeos/ultraestrutura
5.
Int J Nanomedicine ; 14: 4637-4648, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417259

RESUMO

Aim: It has been indicated that NPs may change the amyloidogenic steps of proteins and relevant cytotoxicity. Therefore, this report assigned to explore the impact of ZVFe NPs on the amyloidogenicity and cytotoxicity of α-synuclein as one of the many known amyloid proteins. Methods: The characterization of α-synuclein at amyloidogenic condition either alone or with ZVFe NPs was carried out by fluorescence, CD, UV-visible spectroscopic methods, TEM study, docking, and molecular modeling. The cytotoxicity assay of α-synuclein amyloid in the absence and presence of ZVFe NPs was also done by MTT, LDH, and flow cytometry analysis. Results: ThT fluorescence spectroscopy revealed that ZVFe NPs shorten the lag phase and accelerate the fibrillation rate of α-synuclein. Nile red and intrinsic fluorescence spectroscopy, CD, Congo red adsorption, and TEM studies indicated that ZVFe NP increased the propensity of α-synuclein into the amyloid fibrillation. Molecular docking study revealed that hydrophilic residues, such as Ser-9 and Lys-12 provide proper sites for hydrogen bonding and electrostatic interactions with adsorbed water molecules on ZVFe NPs, respectively. Molecular dynamics study determined that the interacted protein shifted from a natively discorded conformation toward a more packed structure. Cellular assay displayed that the cytotoxicity of α-synuclein amyloid against SH-SY5Y cells in the presence of ZVFe NPs is greater than the results obtained without ZVFe NPs. Conclusion: In conclusion, the existence of ZVFe NPs promotes α-synuclein fibrillation at amyloidogenic conditions by forming a potential template for nucleation, the growth of α-synuclein fibrillation and induced cytotoxicity.


Assuntos
Amiloide/metabolismo , Ferro/química , Nanopartículas Metálicas/química , alfa-Sinucleína/metabolismo , Amiloide/química , Benzotiazóis/química , Morte Celular , Linhagem Celular Tumoral , Vermelho Congo/química , Humanos , Cinética , L-Lactato Desidrogenase/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxazinas/química , Agregados Proteicos , Estrutura Secundária de Proteína , Espectrometria de Fluorescência , Tirosina/química , alfa-Sinucleína/química , alfa-Sinucleína/ultraestrutura
6.
Phys Chem Chem Phys ; 21(28): 15686-15694, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31271401

RESUMO

Alzheimer's disease is associated with the abnormal self-assembly of amyloid-ß (Aß) peptide into toxic oligomers and fibrils. Recent experiments reported that Aß16-22, containing the central hydrophobic core (CHC) of Aß, formed antiparallel ß-sheet fibrils, while its E22Q mutant self-assembled into parallel ß-sheet fibrils. However, the molecular mechanisms underlying E22Q-mutation-induced parallel ß-sheet fibril formation are not well understood. Herein, we performed molecular dynamics (MD) simulations to study the dimerization processes of Aß16-22 and Aß16-22E22Q peptides. ß-Sheet dimers with diverse hydrogen bond arrangements were observed and they exhibited highly dynamic and interconverting properties. An antiparallel-to-parallel ß-sheet transition occurred in the assembly process of the E22Q mutant, but not in that of Aß16-22. During this conformational transformation process, the inter-molecular Q22-Q22 hydrogen bonds were first formed and acted as a binder to facilitate the two chains forming a parallel orientation, then the hydrophobic interactions between residues in the CHC region consolidated this arrangement and drove the main-chain H-bond formation, hence resulting in parallel ß-sheet formation. However, parallel ß-sheets were less populated than antiparallel ß-sheets of Aß16-22E22Q dimers. In order to explore whether parallel ß-sheets became dominant in larger size oligomers, we investigated the conformational ensembles of Aß16-22 and Aß16-22E22Q octamers by conducting replica exchange molecular dynamics (REMD) simulations. The REMD simulations revealed that the population of parallel ß-strand alignment increased with an increase of the size of ordered Aß16-22E22Q ß-sheet oligomers, implying that the formation of full parallel ß-sheets requires larger sized oligomers. Our findings provide a mechanistic explanation for the E22Q-mutation-induced formation of parallel ß-sheet fibrils observed experimentally.


Assuntos
Simulação de Dinâmica Molecular , Mutação , Conformação Proteica em Folha beta/genética , Amiloide/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Humanos , Conformação Proteica
7.
Nat Methods ; 16(7): 611-614, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235884

RESUMO

The study of the aggregation of soluble proteins into highly ordered, insoluble amyloid fibrils is fundamental for the understanding of neurodegenerative disorders. Here, we present a method for the observation of single amyloid fibrils that allows the investigation of fibril growth, secondary nucleation or fibril breakup that is typically hidden in the average ensemble. Our approach of thermophoretic trapping and rotational diffusion measurements is demonstrated for single Aß40, Aß42 and pyroglutamyl-modified amyloid-ß variant (pGlu3-Aß3-40) amyloid fibrils.


Assuntos
Amiloide/química , Agregados Proteicos , Difusão , Dobramento de Proteína
8.
Chem Soc Rev ; 48(14): 3946-3996, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31192324

RESUMO

One of the grand challenges of biophysical chemistry is to understand the principles that govern protein misfolding and aggregation, which is a highly complex process that is sensitive to initial conditions, operates on a huge range of length- and timescales, and has products that range from protein dimers to macroscopic amyloid fibrils. Aberrant aggregation is associated with more than 25 diseases, which include Alzheimer's, Parkinson's, Huntington's, and type II diabetes. Amyloid aggregation has been extensively studied in the test tube, therefore under conditions that are far from physiological relevance. Hence, there is dire need to extend these investigations to in vivo conditions where amyloid formation is affected by a myriad of biochemical interactions. As a hallmark of neurodegenerative diseases, these interactions need to be understood in detail to develop novel therapeutic interventions, as millions of people globally suffer from neurodegenerative disorders and type II diabetes. The aim of this review is to document the progress in the research on amyloid formation from a physicochemical perspective with a special focus on the physiological factors influencing the aggregation of the amyloid-ß peptide, the islet amyloid polypeptide, α-synuclein, and the hungingtin protein.


Assuntos
Amiloide/química , Agregados Proteicos , Agregação Patológica de Proteínas , Animais , Humanos
9.
J Phys Chem Lett ; 10(14): 3836-3842, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31246039

RESUMO

Immunosensors use antibodies to detect and quantify biomarkers of disease, though the sensors often lack structural information. We create a surface-sensitive two-dimensional infrared (2D IR) spectroscopic immunosensor for studying protein structures. We tether antibodies to a plasmonic surface, flow over a solution of amyloid proteins, and measure the 2D IR spectra. The 2D IR spectra provide a global assessment of antigen structure, and isotopically labeled proteins give residue-specific structural information. We report the 2D IR spectra of fibrils and monomers using a polyclonal antibody that targets human islet amyloid polypeptide (hIAPP). We observe two fibrillar polymorphs differing in their structure at the G24 residue, which supports the hypothesis that hIAPP polymorphs form from a common oligomeric intermediate. This work provides insight into the structure of hIAPP, establishes a new method for studying protein structures using 2D IR spectroscopy, and creates a spectroscopic immunoassay applicable for studying a wide range of biomarkers.


Assuntos
Amiloide/química , Técnicas Biossensoriais , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Humanos , Conformação Proteica , Espectrofotometria Infravermelho
10.
Chemphyschem ; 20(13): 1680-1689, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31087613

RESUMO

We employed deuterium solid-state NMR techniques under static conditions to discern the details of the µs-ms timescale motions in the flexible N-terminal subdomain of Aß1-40 amyloid fibrils, which spans residues 1-16. In particular, we utilized a rotating frame (R1ρ ) and the newly developed time domain quadrupolar Carr-Purcell-Meiboom-Gill (QCPMG) relaxation measurements at the selectively deuterated side chains of A2, H6, and G9. The two experiments are complementary in terms of probing somewhat different timescales of motions, governed by the tensor parameters and the sampling window of the magnetization decay curves. The results indicated two mobile "free" states of the N-terminal domain undergoing global diffusive motions, with isotropic diffusion coefficients of 0.7-1 ⋅ 108 and 0.3-3 ⋅ 106 ad2 s-1 . The free states are also involved in the conformational exchange with a single bound state, in which the diffusive motions are quenched, likely due to transient interactions with the structured hydrophobic core. The conformational exchange rate constants are 2-3 ⋅ 105  s-1 and 2-3 ⋅ 104  s-1 for the fast and slow diffusion free states, respectively.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Fragmentos de Peptídeos/química , Deutério , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Domínios Proteicos
11.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071995

RESUMO

Human apolipoprotein E (apoE) is a major component of lipoprotein particles, and under physiological conditions, is involved in plasma cholesterol transport. Human apolipoprotein E found in three isoforms (E2; E3; E4) is a member of a family of apolipoproteins that under pathological conditions are detected in extracellular amyloid depositions in several amyloidoses. Interestingly, the lipid-free apoE form has been shown to be co-localized with the amyloidogenic Aß peptide in amyloid plaques in Alzheimer's disease, whereas in particular, the apoE4 isoform is a crucial risk factor for late-onset Alzheimer's disease. Evidence at the experimental level proves that apoE self-assembles into amyloid fibrilsin vitro, although the misfolding mechanism has not been clarified yet. Here, we explored the mechanistic insights of apoE misfolding by testing short apoE stretches predicted as amyloidogenic determinants by AMYLPRED, and we computationally investigated the dynamics of apoE and an apoE-Αß complex. Our in vitro biophysical results prove that apoE peptide-analogues may act as the driving force needed to trigger apoE aggregation and are supported by the computational apoE outcome. Additional computational work concerning the apoE-Αß complex also designates apoE amyloidogenic regions as important binding sites for oligomeric Αß; taking an important step forward in the field of Alzheimer's anti-aggregation drug development.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/química , Amiloidose/genética , Apolipoproteínas E/química , Doença de Alzheimer/patologia , Amiloide/química , Amiloide/genética , Amiloide/ultraestrutura , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/ultraestrutura , Amiloidose/patologia , Apolipoproteínas E/ultraestrutura , Sítios de Ligação , Colesterol/química , Colesterol/genética , Humanos , Placa Amiloide/genética , Placa Amiloide/patologia , Placa Amiloide/ultraestrutura , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Dobramento de Proteína , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/ultraestrutura
12.
Nanoscale ; 11(18): 9185-9193, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31038146

RESUMO

Recent advances in nanotechnology have developed a lot of opportunities for biological applications. In this work, multifunctional MoS2/AuNR nanocomposites with unique high NIR absorption were designed via combining MoS2 nanosheets and gold nanorods (AuNRs). The nanocomposites were synthesized through electrostatic self-assembly and showed high stability and good biocompatibility. Then they were used to modulate the aggregation of amyloid-ß peptides, destabilize mature fibrils under NIR irradiation, and eliminate Aß-induced ROS against neurotoxicity. The inhibition and destabilization effects were confirmed by Thioflavin T (ThT) fluorescence assay and transmission electron microscopy (TEM). Cell viability assay and ROS assay revealed that MoS2/AuNR nanocomposites could alleviate Aß-induced oxidative stress and cell toxicity. More importantly, both MoS2 nanosheets and AuNRs can be used as NIR photothermal agents, MoS2/AuNR nanocomposites have enhanced ability of disrupting Aß fibrils and improved cell viability by generating local heat under low power NIR irradiation. Our results provide new insights into the design of new multifunctional systems for the treatment of amyloid-related diseases.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Raios Infravermelhos , Nanocompostos/química , Fragmentos de Peptídeos/metabolismo , Amiloide/química , Amiloide/toxicidade , Peptídeos beta-Amiloides/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dissulfetos/química , Ouro/química , Humanos , Molibdênio/química , Nanocompostos/toxicidade , Nanotubos/química , Fragmentos de Peptídeos/química , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
13.
Phys Chem Chem Phys ; 21(22): 11916-11923, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31125036

RESUMO

Peptide structural transformation and aggregation is associated with a large number of outsider aetiology diseases, and it is intrinsically linked to amyloid peptide aggregation. Diphenylalanine self-assembled structures are used as robust minimalist beta amyloids not only to elucidate protein aggregation but also to generate hydrogels. Herein, we employed a neutral model peptide Ac-Phe-Phe-Cys-NH2 (Ac-FFC-NH2) to elucidate the role of intermolecular disulfide bonds in protein fibrillation. The Ac-FFC-NH2 peptide initially self-assembles into nanospheres that evolve to amyloid type fibrils under mild oxidative conditions. Incubation of the peptide in the presence of the chemical reduction agent TCEP inhibits the formation of the fibrils, detecting only spherical nanostructures with no secondary structure. Importantly, we triggered the transformation of the preformed linear straight amyloid fibrils to non-fibrillar structures by TCEP treatment. Under this condition, the amyloid bundles are transformed into rings, which evolve to a new spherical microstructure. We showed that the chemical reduction of intermolecular S-S in internal amyloid sequences might favour the off-path intermediates of amyloid fibril growth, even when the fibrils are formed. Our findings demonstrated that in internal amyloid sequences, the formation of intermolecular S-S promotes the formation of amyloid type fibrils; meanwhile, its reduction stabilises non-fibrillar structures. Altogether, this work provides fundamental understanding at the molecular and supramolecular level, thus facilitating the rational design of therapeutic tools for protein aggregation diseases.


Assuntos
Amiloide/química , Dissulfetos/química , Oligopeptídeos/química , Oligopeptídeos/síntese química , Oxirredução , Multimerização Proteica
14.
J Chem Theory Comput ; 15(6): 3868-3874, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31038946

RESUMO

Thermodynamic stabilities of amyloid fibrils remain mostly unknown due to experimental challenges. Here, we combine enhanced sampling methods to simulate all-atom models in explicit water in order to study the stability of nonpolar (Aß16-21) and polar (IAPP28-33) fibrils. We find that the nonpolar fibril becomes more stable with increasing temperature, and its stability is dominated by entropy. In contrast, the polar fibril becomes less stable with increasing temperature, while it is stabilized by enthalpy. Our results show that the nature of side chains in the dry core of amyloid fibrils plays a dominant role in accounting for their thermodynamic stability.


Assuntos
Amiloide/química , Termodinâmica , Sequência de Aminoácidos , Estudo de Prova de Conceito , Temperatura Ambiente
15.
Int J Biol Macromol ; 132: 929-938, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954597

RESUMO

Elucidating the effects of Al(III) ions on amyloid fibrillation is important to understand the association between metal ions and Alzheimer's disease. Here, Raman spectroscopy was applied to investigate amyloid fibrillation of hen egg-white lysozymes during thermal incubation with Al(III) ions or acids, combined with atomic force microscopy and thioflavin T fluorescence assays. Kinetics of conformational changes in lysozymes were assessed by monitoring six characteristic Raman spectral markers. The peak of Phe residues at 1003 cm-1 and two bands of Trp residues at 759 cm-1 and 1340-1360 cm-1 corresponded to the lysozyme tertiary structure, whereas two NCαC stretching vibrations at 899 cm-1 and 935 cm-1 and an amide I band were associated with the lysozyme skeleton. There may be a four-stage transformation mechanism underlying the kinetics of amyloid fibrillation of lysozymes with the thermal/Al(III) treatment. Comparison of kinetics under thermal/Al(III) and thermal/acid conditions revealed double-edged roles of Al(III) ions in amyloid fibrillation of lysozymes. Specifically, in addition to postponing α-helix degradation, Al(III) ions accelerated conformational transformations from α-helices to organized ß-sheets. The present investigation sheds light on the controversial effects of Al(III) ions on amyloid fibrillation of lysozymes.


Assuntos
Alumínio/química , Alumínio/farmacologia , Amiloide/química , Muramidase/química , Agregados Proteicos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Temperatura Ambiente , Água/química
16.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013856

RESUMO

The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g. neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the patients' quality of life and even causing death. In spite of their clinical diversity, these NDDs share common characteristics, such as the accumulation of specific proteins in the cells, the compromise of the metal ion homeostasis in the brain, among others. Despite considerable advances in understanding the mechanisms of these diseases and advances in the development of treatments, these disorders remain uncured. Considering the diversity of mechanisms that act in NDDs, a wide range of compounds have been developed to act by different means. Thus, promising compounds with contrasting properties, such as chelating agents and metal-based drugs have been proposed to act on different molecular targets as well as to contribute to the same goal, which is the treatment of NDDs. This review seeks to discuss the different roles and recent developments of metal-based drugs, such as metal complexes and metal chelating agents as a proposal for the treatment of NDDs.


Assuntos
Quelantes/farmacologia , Desenvolvimento de Medicamentos , Metais/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Amiloide/química , Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Quelantes/química , Quelantes/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Metais/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Relação Estrutura-Atividade
17.
Mater Sci Eng C Mater Biol Appl ; 101: 169-178, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029310

RESUMO

An electrokinetic potential (ζ-potential) based approach was introduced to address the amyloid degradation on ZnO-nanoflower platform. The hallmark of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease (PD), Creutzfeldt-Jakob Disease (CJD), Prion- associated diseases, type-II diabetes, etc. is the deposition of misfolded protein aggregates predominantly ß-sheeted in structure and fibrillar morphology, known as amyloids, in the brain and different parts of the body. Agents that can degrade these amyloids can be potential candidate for the therapy of amyloidosis. Ultrasmall nanoparticles are gaining interest due to their ability to cross blood brain barrier (BBB) which is favorable for the treatment of neurodegenerative disorders. Considering the influence of Zn2+ in the formation of Aß aggregates instead of fibrillation, the present study was designed based on the ZnO nanoparticles (ZnO-NP) and ZnO nanoflowers (ZnO-NF) to compare the anti amyloid ability using a model huminsulin amyloid. Fluorescence study, atomic force microscopy (AFM), IR spectroscopy (FTIR) and reduction of fibril size using dynamic light scattering showed that ZnO-NF can degrade amyloids with a higher capacity than their nanoparticle counterpart. Significant reduction in magnitude of ζ-potential in ZnO-NF treated huminsulin amyloid supported the notion to come to the consensus and became the new indicator for anti-amyloidosis. The cell viability assay of ZnO-NP and ZnO-NF at a higher dose than that used for amyloid degradation using PC12 and HaCaT cell lines showed their biocompatibility in a safe manner. Thus, it can be suggested that ZnO-NF would be a better candidate for amyloid degradation compared to ZnO-NPs due to higher surface to volume ratio of the petals.


Assuntos
Amiloide/química , Eletroquímica , Nanopartículas/química , Óxido de Zinco/química , Animais , Materiais Biocompatíveis/química , Difusão Dinâmica da Luz , Humanos , Insulina/química , Nanopartículas/ultraestrutura , Células PC12 , Tamanho da Partícula , Proteólise , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
18.
Methods Mol Biol ; 1958: 237-261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30945222

RESUMO

Proteins with prion-like behavior are attracting an increasing interest, since accumulating evidences indicate that they play relevant roles both in health and disease. The self-assembly of these proteins into insoluble aggregates is associated with severe neuropathological processes such as amyotrophic lateral sclerosis (ALS). However, in normal conditions, they are known to accomplish a wide range of functional roles. The conformational duality of prion-like proteins is often encoded in specific protein regions, named prion-like domains (PrLDs). PrLDs are usually long and disordered regions of low complexity. We have shown that PrLDs might contain soft-amyloid cores that contribute significantly to trigger their aggregation, as well as to support their propagation. Further exploration of the role of these sequences in the conformational conversion of prion-like proteins might provide novel insights into the mechanism of action and regulation of these polypeptides, enabling the future development of therapeutic strategies. Here, we describe a set of methodologies aimed to identify and characterize these short amyloid stretches in a protein or proteome of interest, ranging from in silico detection to in vitro and in vivo evaluation and validation.


Assuntos
Biologia Molecular/métodos , Proteínas Priônicas/química , Príons/química , Sequência de Aminoácidos/genética , Amiloide/química , Amiloide/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Humanos , Proteínas Priônicas/genética , Príons/genética , Agregados Proteicos/genética , Domínios Proteicos/genética , Proteoma/química , Proteoma/genética
20.
J Mol Model ; 25(5): 124, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31020417

RESUMO

Besides their biomolecular relevance, amyloids, generated by the self-assembly of peptides and proteins, are highly organized structures useful for nanotechnology applications. The introduction of halogen atoms in these peptides, and thus the possible formation of halogen bonds, allows further possibilities to finely tune the amyloid nanostructure. In this work, we performed molecular dynamics simulations on different halogenated derivatives of the ß-amyloid peptide core-sequence KLVFF, by using a modified AMBER force field in which the σ-hole located on the halogen atom is modeled with a positively charged extra particle. The analysis of equilibrated structures shows good agreement with crystallographic data and experimental results, in particular concerning the formation of halogen bonds and the stability of the supramolecular structures. The modified force field described here allows describing the atomistic details contributing to peptides aggregation, with particular focus on the role of halogen bonds. This framework can potentially help the design of novel halogenated peptides with desired aggregation propensity. Graphical abstract Molecular dynamics investigation of halogenated amyloidogenic peptides.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Simulação de Dinâmica Molecular , Halogenação , Halogênios/química , Modelos Moleculares
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