title: Dual inhibition of BACE1 and Aβ aggregation by β-ecdysone: Application of a phytoecdysteroid scaffold in Alzheimer's disease therapeutics.
abstract: Current medications for the complex neurological disorder, Alzheimer's disease (AD), can neither stop disease progression nor revert back disease pathogenesis. The present study demonstrates the applicability of a phytoecdysteroid, β-ecdysone, as a multi-potent agent in AD therapeutics. β-ecdysone strongly binds to the active site cavity of BACE1 with calculated dissociation constant of 1.75±0.1μM. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of β-ecdysone induces conformational transition of the protein from open to closed form thereby blocking substrate binding. Even 500nM of the compound completely blocks the enzyme activity. Furthermore, β-ecdysone strongly inhibits Aβ aggregation, evident from ANS and ThT binding assay. Co-incubation of equimolar peptide and β-ecdysone completely inhibits Aβ fibril formation which is further complemented by the AFM study. Low systemic toxicity of β-ecdysone further extends the applicability of the compound as functional food and dietary supplement for disease management.
authors.affiliation: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India. Electronic address: sandipanchakraborty.13@gmail.com.
authors.forename: Sandipan
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India. Electronic address: soumalee@gmail.com.
authors.forename: Soumalee
authors.initials: S
authors.lastname: Basu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D004441:Ecdysterone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; C074636:amyloid beta-protein (25-35); D004441:Ecdysterone; D016282:Aspartic Acid Endopeptidases
keywords: AD therapeutics; AFM; Aβ aggregation; BACE1; Molecular modeling; Steady-state and time-resolved fluorescence