Dual inhibition of BACE1 and Aβ aggregation by β-ecdysone: Application of a phytoecdysteroid scaffold in Alzheimer's disease therapeutics

- β-ecdysone strongly binds to the active site and thereby inhibiting BACE1 activity.
- β-ecdysone binding induces open to closed conformational transition of BACE1.
- β-ecdysone also is a strong Aβ aggregation inhibitor, confirmed by AFM study.

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 ± 0.1 μM. 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 500 nM 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.