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

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 (K_a^ITC ∼ 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.