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Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms

Amyloids result from the aggregation of a set of diverse proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is be...

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Autores principales: Giorgetti, Sofia, Greco, Claudio, Tortora, Paolo, Aprile, Francesco Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164555/
https://www.ncbi.nlm.nih.gov/pubmed/30205618
http://dx.doi.org/10.3390/ijms19092677
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author Giorgetti, Sofia
Greco, Claudio
Tortora, Paolo
Aprile, Francesco Antonio
author_facet Giorgetti, Sofia
Greco, Claudio
Tortora, Paolo
Aprile, Francesco Antonio
author_sort Giorgetti, Sofia
collection PubMed
description Amyloids result from the aggregation of a set of diverse proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being exerted in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of β-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs with contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which makes it plausible that more effective drugs will be developed in the future.
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spelling pubmed-61645552018-10-10 Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms Giorgetti, Sofia Greco, Claudio Tortora, Paolo Aprile, Francesco Antonio Int J Mol Sci Review Amyloids result from the aggregation of a set of diverse proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being exerted in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of β-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs with contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which makes it plausible that more effective drugs will be developed in the future. MDPI 2018-09-09 /pmc/articles/PMC6164555/ /pubmed/30205618 http://dx.doi.org/10.3390/ijms19092677 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Giorgetti, Sofia
Greco, Claudio
Tortora, Paolo
Aprile, Francesco Antonio
Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
title Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
title_full Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
title_fullStr Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
title_full_unstemmed Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
title_short Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
title_sort targeting amyloid aggregation: an overview of strategies and mechanisms
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164555/
https://www.ncbi.nlm.nih.gov/pubmed/30205618
http://dx.doi.org/10.3390/ijms19092677
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