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

Authors

Atin Chatterjee, Rajsekhar Roy, Sandip Sarkar, Soumyadeep Sarkar, Amlan Chaini, Arpan Narayan Roy, Batakrishna Jana, Anitha Ethirajan, Uttam Pal, Surajit Barman, Surajit Ghosh, Amitava Das

Published in

Journal of the American Chemical Society. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

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.

PMID:
42339607
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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