MicroRNA-Based Multitarget Approach for Alzheimer’s Disease: Discovery of the First-In-Class Dual Inhibitor of Acetylcholinesterase and MicroRNA-15b Biogenesis

The multitarget approach in drug
design is a powerful strategy
in tackling the multifactorial nature of Alzheimer’s disease
(AD). Herein, we report a novel strategy in the design of multitargeted
therapeutics for AD through dual inhibition of acetylcholinesterase
(AChE) and microRNA-15b biogenesis. We performed high-throughput screening
(HTS) of a chemical library to identify binders of mircoRNA-15b which
is identified as a biomarker and potential therapeutic target of AD.
The hits from HTS were further screened for their AChE inhibitory
activity, the most widely investigated target for the development
of AD therapeutics. MG-6267 was identified as the first dual inhibitor
of AChE and microRNA-15b biogenesis. Cellular assays revealed the
superiority of MG-6267 to single-targeted inhibitors of AChE and microRNA-15b
in protecting SH-SY5Y neuroblastoma cells from amyloid-beta (Aβ)-induced
cytotoxicity. This work paves the way for future research efforts
aiming at the development of microRNA-based multitargeted therapeutics
for AD.