Coassembly of Macrocyclic Amphiphiles for Anti-β-Amyloid Therapy of Alzheimer’s Disease

Abstract

Based on the amyloid hypothesis, anti-β-amyloid (Aβ) therapy has dominated clinical trials for the prevention and treatment of Alzheimer's disease (AD) in recent years. A key element of this strategy is the interaction between therapeutic agents and Aβ. However, the design and development of artificial receptors that may render selective and strong recognition toward Aβ remains a huge challenge because of the complexity and size of peptide guests and their flexible conformation. To address this issue, we fabricated a coassembly of two kinds of macrocyclic amphiphiles, guanidinium-modified calixarene (GCA) and cyclodextrin (CD). The GCA-CD coassembly exhibited extraordinarily strong binding affinity to Aβ with exquisite specificity benefiting from the heteromultivalent recognition. As a result, GCA-CD was capable of completely inhibiting the fibrillation of Aβ and disintegrating mature fibrils, and moreover, effectively mitigated the cytotoxicity induced by Aβ fibrils and improved the cognitive deficit of AD mice.The potential of GCA-CD as a therapeutic agent for the treatment of AD was witnessed both in vitro and in vivo.

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