The pathogenesis of Alzheimer's disease (AD) is closely related to several contributing factors, especially amyloid-β (Aβ) aggregation. Bioorthogonal reactions provide a general, facile, and robust route for the localization and derivatization of Aβ-targeted agents. Herein, a pair of chiral alkyne-containing metallohelices (ΛA and ΔA) were demonstrated to enantioselectively target and modulate Aβ aggregation, which has been monitored in triple-transgenic AD model mice and proved to improve cognitive function. Compared with its enantiomer ΔA, ΛA performed better in blocking Aβ fibrillation, relieving Aβ-triggered toxicity, and recovering memory deficits in vivo. Moreover, clickable ΛA could act as a functional module for subsequent visualization and versatile modification of amyloid via bioorthogonal reaction. As a proof-of-concept, thioflavin T, tacrine, and magnetic nanoparticles were conjugated with ΛA to realize Aβ photo-oxygenation, acetylcholinesterase inhibition, and Aβ clearance, respectively. This proof-of-principle work provided new insights into the biolabeling and bioconjugation of multifunctional metallosupramolecules through click reactions for AD therapy.
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