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.

Giorgetti, S., Greco, C., Tortora, P., Aprile, F. (2018). Targeting amyloid aggregation: An overview of strategies and mechanisms. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19(9), 2677 [10.3390/ijms19092677].

Targeting amyloid aggregation: An overview of strategies and mechanisms

Greco, C;Tortora, P
;
Aprile, FA
2018

Abstract

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.
Articolo in rivista - Review Essay
Amyloid diseases; Biocomputing; Drug design; Natural antiamyloids; Catalysis; Molecular Biology; Spectroscopy; Computer Science Applications; Computer Vision and Pattern Recognition; Physical and Theoretical Chemistry; Organic Chemistry; Inorganic Chemistry
English
2018
19
9
2677
2677
partially_open
Giorgetti, S., Greco, C., Tortora, P., Aprile, F. (2018). Targeting amyloid aggregation: An overview of strategies and mechanisms. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19(9), 2677 [10.3390/ijms19092677].
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