Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity

Abstract

Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC50 of 1.5 ± 0.3 μM, which was smaller than that of (−)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ42 fibrillogenesis by directly binding to Aβ42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease.

Computational design and evaluation of β‐sheet breaker peptides for destabilizing Alzheimer's amyloid‐β42 protofibrils

“…The pentameric model has been used in computational investigations to elucidate the action of inhibitors on Aβ 17-42 protofibril structure. 23,24 For molecular docking of pentapeptides with Aβ 42 protofibril, PDBQT files for the receptor and pentapeptides were prepared using PyRx-Virtual screening tool. 25 PyRx includes docking wizard with a graphical user interface (GUI), which makes it a valuable tool in computer-aided drug design (CADD).…”

Production of Whey Protein-Based Aggregates Under Ohmic Heating

“…Moreover, the non-thermal effects of OH seem to be also linked with conformational changes of secondary protein structures, by increasing the contents of β-sheet structures (Pereira et al, 2010) which have been recently associated with the formation of β-lg fibrils during heating at 80 °C or prolonged incubation with chemical denaturants (Kavanagh et al, 2000). Protein aggregates possessing a fibrillar structure have attracted attention in biomedical and materials science fields, as they may resemble amyloid aggregates implicated in protein misfolding disorders, also known as amyloidosis diseases, e.g., Alzheimer's, Creutzfeldt-Jakob, and Huntington's diseases (Chimon et al 2007;Du et al 2015;Hamada and Dobson 2002;Loveday et al 2012). Results show that OH may have the potential to enhance β-lg fibril formation when performed under certain conditions aforementioned (such as prolonged heating at pH < 3 and low ionic strength), but this hypothesis needs to be further verified.…”

Brazilin Inhibits Prostatic Acidic Phosphatase Fibrillogenesis and Decreases its Cytotoxicity

“…Recently,w ed emonstrated that brazilin (Figure 1), an atural compound that is isolated from Caesalpinia sappan, is ap otent inhibitor of amyloid b-protein fibrillogenesis and shows astronger inhibition effect at lower concentrationst han EGCG. [13] Amyloid b-protein is highly hydrophobic, whilst PAP 248-286 is hydrophilic. Hence, it would be interesting to investigate if this small molecule is also effective at inhibiting the aggregation of [a] M.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.…”