Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms

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.

Track‐Etched Nanopore/Membrane: From Fundamental to Applications

“…[ 261 ] Figure a shows the aggregation process of amyloid proteins, including four steps among which the intermediates are the most toxic. [ 262 ] The analysis of the formation of amyloid intermediates is achieved using PEG‐functionalized conical nanopores where PEG chains are used as antifouling coatings (Figure 16b). [ 258 ] By continuous translocating solutions containing initially only monomers, a change in event distributions is observed as shown in Figure 16c.…”

Comparative study of the stabilities of synthetic in vitro and natural ex vivo transthyretin amyloid fibrils

“…Most of our knowledge of the pathogenesis of TTR amyloidosis derives from the experimental model of in vitro fibrillogenesis at low pH in which protein aggregation is primed by tetramer disassembly (3); this method has been the key tool for identifying drugs, such as tafamidis, currently used to treat the disease (4-7). More recently, based on the observation that truncated forms of TTR are present in natural fibrils (8), we have established a new, more physiological, system of fibrillogenesis in which biomechanical forces combined with specific proteolytic enzymes play a central role (9)(10)(11).…”

Daurichromenic Acid from the Chinese Traditional Medicinal Plant Rhododendron dauricum Inhibits Sphingomyelin Synthase and Aβ Aggregation

“…The chemical similarity of ginkogolic acid to DCA, as it is a long alkyl chain and a carboxylic acid moiety in an aromatic ring, shows that these two inhibitors also have the same functional group participation to inhibit SMS. Further, a previous report [ 26 ] concerning the mode of action for Aβ aggregation inhibition for small molecules gave the insight that the crucial role of a hydrophobic-side hydrocarbon chain and an aromatic ring as well as its two hydrophilic functions causes significant interaction with the amyloid.…”