title: 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.
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Du
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Guo
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Ming-Tao
authors.initials: MT
authors.lastname: Gao
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China.
authors.forename: Sheng-Quan
authors.initials: SQ
authors.lastname: Hu
authors.affiliation: 1] Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China [2] Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Dong
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Han
authors.affiliation: 1] Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China [2] Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.
authors.forename: Fu-Feng
authors.initials: FF
authors.lastname: Liu
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195-1750, USA.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Jiang
authors.affiliation: 1] Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China [2] Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D055503:Protein Multimerization
chemical_list: D016229:Amyloid beta-Peptides; D001578:Benzopyrans; C044362:brazilin