Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Abstract

The formation of amyloid aggregates is responsible for a wide range of diseases, including Alzheimer's and Parkinson's disease. Although the amyloid-forming proteins have different structures and sequences, all undergo a conformational change to form amyloid aggregates that have a characteristic cross-β-structure. The mechanistic details of this process are poorly understood, but different strategies for the development of inhibitors of amyloid formation have been proposed. In most cases, chemically diverse compounds bind to an elongated form of the protein in a β-strand conformation and thereby exert their therapeutic effect. However, this approach could favor the formation of prefibrillar oligomeric species, which are thought to be toxic. Herein, we report an alternative approach in which a helical coiled-coil-based inhibitor peptide has been designed to engage a coiled-coil-based amyloid-forming model peptide in a stable coiled-coil arrangement, thereby preventing rearrangement into a β-sheet conformation and the subsequent formation of amyloid-like fibrils. Moreover, we show that the helix-forming peptide is able to disassemble mature amyloid-like fibrils.

para‐Sulfonatocalix[n]arenes Inhibit Amyloid β‐Peptide Fibrillation and Reduce Amyloid Cytotoxicity

“…Further reduction of the fluorescence intensities was observed with increasingc oncentrations of the SC[n]A. In general,a ll three SC[n]As showeds trong effects, but the effectiveness order was likely to be SC[8]A > SC [6]A > SC [4]A. To reduce the fluorescencei ntensities by 50 %, about 250 mm SC[8]A, 1250 mm SC [6]A, and 2500 mm SC[4]A were required.…”

“…[5] Moreover,i ti sg enerally accepted that soluble Ab oligomers or protofibrils are the most toxic speciesa nd are responsible for neuron dysfunction and death. [6] Therefore, inhibition of Ab aggregation at av ery early stage could be ap romisingt reatment for preventing or delaying the onset of AD. [7] Significant efforts have been made to developd ifferentamyloid inhibitors, including small organic compounds, [8] peptides, [9] antibodies, [10] andn anoparticles.…”

“…[17] para-Sulfonatocalix[n]arene (SC[n]A;s ee the Supporting Information), another kind of macrocycle, possesses al arge hydrophobic cavity with phenolic hydroxyl groups at the lower rim and negatively charged sulfonate groups at the upper rim. Because of their high water solubility, [18] low toxicity, [19] and good biocompatibility, [20] SC [4]A, SC [6]A, and SC[8]A have been widelyi nvestigated forb iological and biomedical applications. [21] The three macrocycles have been known to form complexesw ith numerousg uest molecules through noncovalent interactions.…”

Concluding the Amyloid Formation Pathway of a Coiled‐Coil‐Based Peptide from the Size of the Critical Nucleus

“…A nucleus consisting of oligomeric aggregates can also be formed by native or native-like structures, and the conversion to amyloids subsequently takes place within the aggregates. [36][37][38] Here we calculated the nucleus size of a model peptide that has been previously established and well characterized in our group, [46][47][48][49][50][51][52][53] VW18, by applying the nucleated growth polymerization theory to experimental data. A wide range of experimental strategies is currently being developed to detect the actual nucleus size.…”

“…[49] TANGO is able to identify aggregationprone regions in the primary sequence and indicate competing structural propensities, such as for helix or b-sheet formation. It can be assumed that the hydrophobic central part of the sequence (LVVL) adopts a bsheet conformation first, as this segment has been predicted with the computer algorithms TANGO to have the highest tendency to aggregate.…”