Supramolecular Integration of 18-Crown-6 and an N-Capped Short Peptide Enables Multivalent Recognition and Modulation of Amyloid-β Proteotoxicity.

Amyloid-β 42 (Aβ-42) misfolding and self-assembly drive proteostatic collapse in Alzheimer's disease, but chemically programmable systems enabling sequence-selective recognition and remodeling of the Aβ-42 aggregation pathway remain elusive. We report a rationally engineered supramolecular composite, 18C6-LV-PEG, that integrates benzo-18-crown-6 (18C6) to form a supramolecular inclusion complex with the ε-NH3+ group on lysine, a short peptide sequence targeting the 17LVFF20 motif of Aβ-42, and a PEG appendage to enhance pharmacokinetics and blood-brain barrier permeability. Cooperative multivalent engagement of this motif, confirmed by 1H-15N HSQC NMR, confers markedly enhanced affinity (KaITC ∼ 7.4 × 104 M-1 toward monomeric Aβ-42) relative to individual components (≤102 M-1), demonstrating synergistic binding. Importantly, 18C6-LV-PEG not only blocks nucleation-dependent Aβ-42 aggregation but also effectively destabilizes soluble oligomers, as well as mature aggregates, revealing a mechanistically distinct supramolecular modulation of the Aβ-42 aggregation pathway relative to conventional inhibitors. The nontoxic conjugate mitigates oxidative stress, restores mitochondrial function, reinstates glial-neuronal connectivity, and improves cognition in an Alzheimer's model. More broadly, this work introduces a conceptual design principle that integrates precision Lys16-clamp by 18C6 with targeting of the aggregation-prone 17LVFF20 motif to enable chemically programmable, multivalent intervention in pathogenic protein assemblies.