Abstract
The study of compounds able to interfere in various ways with amyloid aggregation is of paramount importance in amyloid research. Molecules characterized by a 4-thiaflavane skeleton have received great attention in chemical, medicinal, and pharmaceutical research. Such molecules, especially polyhydroxylated 4-thiaflavanes, can be considered as structural mimickers of several natural polyphenols that have been previously demonstrated to bind and impair amyloid fibril formation. In this work, we tested five different 4-thiaflavanes on the hen egg-white lysozyme (HEWL) amyloid model for their potential anti-amyloid properties. By combining a thioflavin T assay, atomic force microscopy, and a cell toxicity assay, we demonstrated that such compounds can impair the formation of high-order amyloid aggregates and mature fibrils. Despite this, the tested 4-thiaflavanes, although non-toxic per se, are not able to prevent amyloid toxicity on human neuroblastoma cells. Rather, they proved to block early aggregates in a stable, toxic conformation. Accordingly, 4-thiaflavanes can be proposed for further studies aimed at identifying blocking agents for the study of toxicity mechanisms of amyloid aggregation.
Highlights
Amyloid aggregation is a degenerative process characterized by deposition at tissue levels of organized insoluble super-molecular protein assemblies with a typical cross-β secondary structure.Such degeneration gives rise to amyloidosis, a composite range of diseases classically divided into neurodegenerative (e.g., Alzheimer’s disease, Parkinson’s disease, etc.) and systemic amyloidosis
In order to study the morphology of the hen egg-white lysozyme (HEWL) amyloid aggregates after 10 days, we deposited the aggregating solutions on freshly cleaved mica and its surface was scanned by AFM
Discussion disease or Parkinson’s disease as well as systemic diseases such as reactive systemic amyloidosis, TTR, and light chain amyloidosis are increasingly recognized as important death factors for public health systems
Summary
Amyloid aggregation is a degenerative process characterized by deposition at tissue levels of organized insoluble super-molecular protein assemblies with a typical cross-β secondary structure. Wild-type lysozyme is not directly involved in amyloid diseases, several naturally lysozyme either from humans, horses, orIle56Thr, hens, under appropriate conditions, is able are to form amyloid occurring single point mutations (e.g., Phe57Ile, Trp64Arg, and Asp67His) connected with fibrils in vitro [9,10,11]. The fact thatand notinduce associated with in vivo [13], it has been leading to the formation oftemperatures peptide fragments Such fragments have atohigh to the mutated formationinofhuman peptidefamiliar fragments Aggregation for their ability to induce quinoprotein formation [26]
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