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.