Discovery of Natural Product-Based Amyloid Inhibitors

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (25 January 2024) | Viewed by 7273

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Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy
Interests: amyloid aggregation; autophagy; natural polyphenols; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

The positive actions of nutritional supplements and plant extracts in disease prevention are now mainstream and commercial health claims that are being made are subject to strict regulation in most countries. In recent years, increasing interest has been focused on plant polyphenols not only for their antioxidant properties but also due to their ability to inhibit amyloid fibril growth, to favor their disaggregation and to destabilize preformed fibrils. Polyphenols have been shown to abrogate self-assembly of several peptides/proteins associated with amyloid diseases (systemic or neurodegenerative diseases) in different ways depending on the molecular features of either component. The findings reported in the last decade are starting to help to decipher the complex relations between plant polyphenols and protein amyloid aggregation establishing an increasingly solid molecular basis for the healthy effects of these molecules. In fact, several clinical trials have confirmed that most of the benefits of the Mediterranean/Asian diets can be traced back to the presence of significant amounts of these molecules, even though, in some cases, contradictory results have been reported, which highlights the need to provide further investigation on the biochemical, molecular and cell biology modifications by plant polyphenols in models of amyloid diseases.

Dr. Manuela Leri
Guest Editor

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Keywords

  • amyloid aggregation
  • polyphenols
  • neurodegenerative diseases
  • systemic diseases

Published Papers (3 papers)

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Research

17 pages, 3165 KiB  
Article
The Transthyretin/Oleuropein Aglycone Complex: A New Tool against TTR Amyloidosis
by Francesco Bemporad, Manuela Leri, Matteo Ramazzotti, Massimo Stefani and Monica Bucciantini
Pharmaceuticals 2022, 15(3), 277; https://doi.org/10.3390/ph15030277 - 23 Feb 2022
Cited by 3 | Viewed by 1648
Abstract
The release of monomers from the homotetrameric protein transthyretin (TTR) is the first event of a cascade, eventually leading to sporadic or familial TTR amyloidoses. Thus, ligands able to stabilize TTR and inhibit monomer release are subject of intense scrutiny as potential treatments [...] Read more.
The release of monomers from the homotetrameric protein transthyretin (TTR) is the first event of a cascade, eventually leading to sporadic or familial TTR amyloidoses. Thus, ligands able to stabilize TTR and inhibit monomer release are subject of intense scrutiny as potential treatments against these pathologies. Here, we investigated the interaction between TTR and a non-glycated derivative of the main olive polyphenol, oleuropein (OleA), known to interfere with TTR aggregation. We coupled fluorescence studies with molecular docking to investigate the OleA/TTR interaction using wild-type TTR, a monomeric variant, and the L55P cardiotoxic mutant. We characterized a fluorescence band emitted by OleA upon formation of the OleA/TTR complex. Exploiting this signal, we found that a poorly specific non-stoichiometric interaction occurs on the surface of the protein and a more specific stabilizing interaction takes place in the ligand binding pocket of TTR, exhibiting a KD of 3.23 ± 0.32 µM, with two distinct binding sites. OleA interacts with TTR in different modes, stabilizing it and preventing its dissociation into monomers, with subsequent misfolding. This result paves the way to the possible use of OleA to prevent degenerative diseases associated with TTR misfolding. Full article
(This article belongs to the Special Issue Discovery of Natural Product-Based Amyloid Inhibitors)
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12 pages, 5042 KiB  
Article
Evaluation of Amyloid Polypeptide Aggregation Inhibition and Disaggregation Activity of A-Type Procyanidins
by Taisei Tanaka, Vipul V. Betkekar, Ken Ohmori, Keisuke Suzuki and Hideyuki Shigemori
Pharmaceuticals 2021, 14(11), 1118; https://doi.org/10.3390/ph14111118 - 31 Oct 2021
Cited by 9 | Viewed by 2376
Abstract
The number of people worldwide suffering from Alzheimer’s disease (AD) and type 2 diabetes (T2D) is on the rise. Amyloid polypeptides are thought to be associated with the onset of both diseases. Amyloid-β (Aβ) that aggregates in the brain and human islet amyloid [...] Read more.
The number of people worldwide suffering from Alzheimer’s disease (AD) and type 2 diabetes (T2D) is on the rise. Amyloid polypeptides are thought to be associated with the onset of both diseases. Amyloid-β (Aβ) that aggregates in the brain and human islet amyloid polypeptide (hIAPP) that aggregates in the pancreas are considered cytotoxic and the cause of the development of AD and T2D, respectively. Thus, inhibiting amyloid polypeptide aggregation and disaggregation existing amyloid aggregates are promising approaches in the therapy and prevention against both diseases. Therefore, in this research, we evaluated the Aβ/hIAPP anti-aggregation and disaggregation activities of A-type procyanidins 17 and their substructures 8 and 9, by conducting structure–activity relationship studies and identified the active site. The thioflavin-T (Th-T) assay, which quantifies the degree of aggregation of amyloid polypeptides based on fluorescence intensity, and transmission electron microscopy (TEM), employed to directly observe amyloid polypeptides, were used to evaluate the activity. The results showed that catechol-containing compounds 16 exhibited Aβ/hIAPP anti-aggregation and disaggregation activities, while compound 7, without catechol, showed no activity. This suggests that the presence of catechol is important for both activities. Daily intake of foods containing A-type procyanidins may be effective in the prevention and treatment of both diseases. Full article
(This article belongs to the Special Issue Discovery of Natural Product-Based Amyloid Inhibitors)
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15 pages, 2548 KiB  
Article
Flavanonol Glycosides from the Stems of Myrsine seguinii and Their Neuroprotective Activities
by Hee-Ju Lee, Eun-Jin Park, Ba-Wool Lee, Hyo-Moon Cho, Thi-Linh-Giang Pham, Quynh-Hoa Hoang, Cheol-Ho Pan and Won-Keun Oh
Pharmaceuticals 2021, 14(9), 911; https://doi.org/10.3390/ph14090911 - 9 Sep 2021
Cited by 1 | Viewed by 2375
Abstract
The accumulation of amyloid beta (Aβ) peptides is common in the brains of patients with Alzheimer’s disease, who are characterized by neurological cognitive impairment. In the search for materials with inhibitory activity against the accumulation of the Aβ peptide, seven [...] Read more.
The accumulation of amyloid beta (Aβ) peptides is common in the brains of patients with Alzheimer’s disease, who are characterized by neurological cognitive impairment. In the search for materials with inhibitory activity against the accumulation of the Aβ peptide, seven undescribed flavanonol glycosides (17) and five known compounds (812) were isolated from stems of Myrsine seguinii by HPLC-qTOF MS/MS-based molecular networking. Interestingly, this plant has been used as a folk medicine for the treatment of various inflammatory conditions. The chemical structures of the isolated compounds (112) were elucidated based on spectroscopic data, including 1D and 2D nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS) and electronic circular dichroism (ECD) data. Compounds 2, 6 and 7 showed neuroprotective activity against Aβ-induced cytotoxicity in Aβ42-transfected HT22 cells. Full article
(This article belongs to the Special Issue Discovery of Natural Product-Based Amyloid Inhibitors)
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