Dual inhibition of BACE1 and A beta aggregation by beta-ecdysone: Application of a phytoecdysteroid scaffold in Alzheimer%26apos;s disease therapeutics

作者：Chakraborty Sandipan; Basu Soumalee

来源：International Journal of Biological Macromolecules, 2017, 95: 281-287.

DOI：10.1016/j.ijbiomac.2016.11.061

• AD therapeutics
• BACE1
• A beta aggregation
• Steady-state and time-resolved
• fluorescence
• Molecular modeling
• AFM

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, beta-ecdysone, as a multi-potent agent in AD therapeutics. beta-ecdysone strongly binds to the active site cavity of BACE1 with calculated dissociation constant of 1.75 +/- 0.1 mu M. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of beta-ecdysone induces conformational transition of the protein from open to closed form thereby blocking substrate binding. Even 500 nM of the compound completely blocks the enzyme activity. Furthermore, beta-ecdysone strongly inhibits A beta aggregation, evident from ANS and ThT binding assay. Co-incubation of equimolar peptide and beta-ecdysone completely inhibits A beta fibril formation which is further complemented by the AFM study. Low systemic toxicity of beta-ecdysone further extends the applicability of the compound as functional food and dietary supplement for disease management.

• 出版日期2017-2