A Prodrug Approach for Activity-Based Chemical Modulation toward Multiple Pathological Targets in Alzheimer's Disease.

Targeting disease-specific chemical signals enables precise therapeutic control over complex pathologies. In Alzheimer's disease (AD), elevated hydrogen peroxide (H2O2) accompanies hallmark features, including amyloid-β (Aβ) aggregate deposition and metal ion dyshomeostasis, creating an oxidative milieu primed for selective chemical activation. Here, we show a rationally designed prodrug platform that harnesses H2O2 as an endogenous trigger for redox-based therapy. Boronic ester-masked precursors (BE-1 and BE-2) remain inert under physiological conditions but undergo rapid oxidative deboronation in the presence of H2O2, releasing redox-active aminophenols. These activated molecules exhibit multimodal pathological modulation, as revealed by molecular-level biochemical and biophysical analyses: scavenging reactive oxygen species, inducing residue-specific oxidative modifications of Aβ, and redirecting aggregation pathways of both metal-free and metal-bound Aβ. In AD transgenic mice, BE-1 undergoes conversion to its active form within the brain tissue. Long-term administration of BE-1 markedly reduces hippocampal oxidative stress, lowers amyloid plaque burden, and improves cognitive performance. This pathology-responsive, activity-based prodrug strategy provides a chemically precise framework for simultaneously modulating multiple, interconnected drivers of neurodegeneration.