title: HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity.
abstract: Amyloid deposits of misfolded amyloid-β protein (Aβ) on neuronal cells are a pathological hallmark of Alzheimer's disease (AD). Prevention of the abnormal Aβ aggregation has been considered as a promising therapeutic strategy for AD treatment. To prevent reinventing the wheel, we proposed to search the existing drug database for other diseases to identify potential Aβ inhibitors. Herein, we reported the inhibitory activity of HP-β-cyclodextrin (HP-β-CD), a well-known sugar used in drug delivery, genetic vector, environmental protection and treatment of Niemann-Pick disease type C1 (NPC1), against Aβ1-42 aggregation and Aβ-induced toxicity, with the aim of adding a new function as a sugar-based Aβ inhibitor. Experimental data showed that HP-β-CD molecules were not only nontoxic to cells, but also greatly inhibited Aβ fibrillization and reduced Aβ-induced toxicity in a concentration-dependent manner. At an optimal molar ratio of Aβ : HP-β-CD = 1 : 2, HP-β-CD enabled the reduction of 60% of Aβ fibrils and increased the cell viability to 92%. Such concentration-dependent inhibitor capacity of HP-β-CD was likely attributed to several combined effects, including the enhancement of Aβ-HP-β-CD interactions, prevention of structural transition of Aβ peptides towards β-sheet structures, and reduction of self-aggregation of HP-β-CD. In parallel, molecular simulations further revealed the atomic details of HP-β-CD interacting with the Aβ oligomer, showing that HP-β-CD had a high tendency to interact with hydrophobic residues of Aβ in two β-strands and the N-terminal tail. More importantly, we identified that the inner hydrophobic cavity of HP-β-CD was a key active site for Aβ inhibition. Once the inner cavity of HP-β-CD was blocked by a small hydrophobic molecule of ferulic acid, HP-β-CD completely lost its inhibition capacity against Aβ. Given the already established pharmaceutical functions of HP-β-CD in drug delivery, our findings suggest that HP-β-CD has great potential to be designed as a sugar-based Aβ inhibitor.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China and Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
authors.forename: Baiping
authors.initials: B
authors.lastname: Ren
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China and Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
authors.forename: Binbo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
authors.forename: Rundong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse, School of Environmental Science and Engineering, Tongji University, Shanghai 200092, China and Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
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: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066263:Protein Aggregation, Pathological / Q000188:drug therapy; D047392:beta-Cyclodextrins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D047392:beta-Cyclodextrins