Du_2023_Chem.Sci_14_506

The pathogenesis of Alzheimer's disease (AD) is closely related to several contributing factors, especially amyloid-beta (Abeta) aggregation. Bioorthogonal reactions provide a general, facile, and robust route for the localization and derivatization of Abeta-targeted agents. Herein, a pair of chiral alkyne-containing metallohelices (A and deltaA) were demonstrated to enantioselectively target and modulate Abeta aggregation, which has been monitored in triple-transgenic AD model mice and proved to improve cognitive function. Compared with its enantiomer deltaA, A performed better in blocking Abeta fibrillation, relieving Abeta-triggered toxicity, and recovering memory deficits in vivo. Moreover, clickable A 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 A to realize Abeta photo-oxygenation, acetylcholinesterase inhibition, and Abeta clearance, respectively. This proof-of-principle work provided new insights into the biolabeling and bioconjugation of multifunctional metallosupramolecules through click reactions for AD therapy.