Non-polyphenolic natural inhibitors of amyloid aggregation

Ma, Liang; Yang, Chen; Zheng, Jiaojiao; Chen, Yu‐Chen; Xiao, Yushuo; Huang, Kun

doi:10.1016/j.ejmech.2020.112197

Cited by 50 publications

(58 citation statements)

References 273 publications

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“…A rich and important literature (Ma et al, 2020;Muscat et al, 2020b;Stefanescu et al, 2020) reports both experimental and computational studies, focused on the effects of natural compounds on different self-aggregated Aβ species. We have reviewed here those studies in which the proposed molecular mechanism of action is supported by a combination of biophysical approaches and experimental structural data.…”

Section: Natural Compounds With Inhibitory Effects On Aβ Peptide Aggrmentioning

confidence: 99%

“…Small molecules from natural sources, effective in inhibiting Aβ aggregation, belong to different classes of chemical compounds, although polyphenols appear to be the most represented class (see Table 1). They can affect one or multiple aggregation stages by directly interacting with Aβ peptide through non-covalent and/or covalent interactions (Ma et al, 2020). Polyphenols ability to hamper Aβ aggregation has been attributed to the combined action of the phenolic moieties, that can π-π stack or interact hydrophobically with Aβ aromatic residues and insert into the space of Aβ aggregates, and/or interact via hydrogen bonding through phenolic hydroxyl groups (Fan et al, 2020 and references therein).…”

Section: Ligand-epitopes Involved In the Interaction With Aβmentioning

confidence: 99%

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Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Pagano¹,

Tomaselli²,

Molinari³

et al. 2020

Front. Neurosci.

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Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-β (Aβ) peptides are recognized as the main cause of AD progression, leading to the formation of toxic Aβ oligomers and to the deposition of β-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with Aβ aggregation by direct interaction with Aβ peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the Aβ regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and β1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

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Section: Natural Compounds With Inhibitory Effects On Aβ Peptide Aggrmentioning

confidence: 99%

Section: Ligand-epitopes Involved In the Interaction With Aβmentioning

confidence: 99%

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Pagano¹,

Tomaselli²,

Molinari³

et al. 2020

Front. Neurosci.

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“…In its monomeric soluble form, α-syn assumes an alpha helical conformation upon interaction with phospholipids, 7 while in the pathological misfolded state, it aggregates into amyloid fibrils composed by parallel hydrogen bonded β-sheets 8 , 9 . The formation of these aggregates causes cytotoxicity through lipid membrane permeabilisation, mitochondrial damage and oxidative stress 10 . Another relevant mechanism that contributes to the propagation of neurodegeneration is the prion-like spread of α-syn aggregates.…”

Section: Introductionmentioning

confidence: 99%

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Vittorio

Adornato

Gitto

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Parkinson’s disease is one of the most common neurodegenerative disorders in elderly age. One of the mechanisms involved in the neurodegeneration appears related to the aggregation of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To date, no highly effective treatment is currently available; therefore, there is an increasing interest in the search of new therapeutic tools. The modulation of α-syn aggregation represents an emergent and promising disease-modifying strategy for reducing or blocking the neurodegenerative process. Herein, by combining in silico and in vitro screenings we initially identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine ( 3 ) as α-syn aggregation inhibitor that was then considered a promising hit for the further design of a new series of small molecules. Therefore, we rationally designed new hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the binding mode of the newer inhibitors was predicted by docking studies.

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“…Current data on amyloid-beta plaque formation, which is characterized by misfolding, aggregation, and deposition of Aβ peptide and leads to cellular dysfunction, loss of synaptic transmission, and brain impairment indicate that AD is one of the protein misfolding disorders (PMDs). A recent step forward in the field was obtained through experimental results indicating that misfolded protein aggregates such as amyloid-beta in AD, human islet amyloid polypeptide in type 2 diabetes, or α-synuclein in Parkinson’s disease could self-disseminate by seeding and spread the pathological deficits between cells and tissues [ 3 , 4 ]. This breakthrough has broad implications for understanding the pathways implicated in the onset and evolution of AD, as well as for the design of new plans and strategies for treatment and diagnosis [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the amyloid fibrils, the amino-terminal end of the amyloid-beta peptide is exposed to the interaction with other molecules, while the middle region and the carboxyl-terminal end of the peptide are involved in intramolecular and intermolecular interactions between molecules of Aβ [ 9 ]. Molecules which belong to various classes were analyzed in previous studies as non-covalent binding partners for Aβ peptide: antibodies, peptides, proteins and low molecular weight molecules [ 3 , 4 , 8 , 10 ]. The methods employed most often for comparing aggregation, and particularly amyloid fibril formation using different experimental conditions, are the thioflavin T assay ( Figure 1 ), transmission electron microscopy, atomic force microscopy, and scanning electron microscopy.…”

Section: Introductionmentioning

confidence: 99%

Secondary Metabolites from Plants Possessing Inhibitory Properties against Beta-Amyloid Aggregation as Revealed by Thioflavin-T Assay and Correlations with Investigations on Transgenic Mouse Models of Alzheimer’s Disease

et al. 2020

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Alzheimer’s disease is a neurodegenerative disorder for which there is a continuous search of drugs able to reduce or stop the cognitive decline. Beta-amyloid peptides are composed of 40 and 42 amino acids and are considered a major cause of neuronal toxicity. They are prone to aggregation, yielding oligomers and fibrils through the inter-molecular binding between the amino acid sequences (17–42) of multiple amyloid-beta molecules. Additionally, amyloid deposition causes cerebral amyloid angiopathy. The present study aims to identify, in the existing literature, natural plant derived products possessing inhibitory properties against aggregation. The studies searched proved the anti-aggregating effects by the thioflavin T assay and through behavioral, biochemical, and histological analysis carried out upon administration of natural chemical compounds to transgenic mouse models of Alzheimer’s disease. According to our present study results, fifteen secondary metabolites from plants were identified which presented both evidence coming from the thioflavin T assay and transgenic mouse models developing Alzheimer’s disease and six additional metabolites were mentioned due to their inhibitory effects against fibrillogenesis. Among them, epigallocatechin-3-gallate, luteolin, myricetin, and silibinin were proven to lower the aggregation to less than 40%.

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Non-polyphenolic natural inhibitors of amyloid aggregation

Cited by 50 publications

References 273 publications

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Secondary Metabolites from Plants Possessing Inhibitory Properties against Beta-Amyloid Aggregation as Revealed by Thioflavin-T Assay and Correlations with Investigations on Transgenic Mouse Models of Alzheimer’s Disease

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