A hydrogel model constructed from the Aβ core peptide was degraded using enediyne derivatives to validate their peptide cleavage capabilities through cycloaromatization. The radical mediated mechanism for backbone scission and modification was demonstrated by HPLC-MS fragmentation analysis, offering a novel therapeutic approach for Alzheimer's disease.

Abstract

A hallmark pathological feature of Alzheimer's disease is the aberrant aggregation of amyloid-beta (Aβ) protein. While current therapeutics that target the imbalance between Aβ synthesis and clearance demonstrate the ability to clear amyloid plaques, their limited clinical efficacy underscores the need for alternative approaches that directly disrupt Aβ aggregates. In this study, we employed a hydrogel model constructed from the Aβ core peptide to validate the peptide cleavage capability of enediyne derivatives, followed by high-resolution liquid chromatography-mass spectrometry analysis of the resulting cleavage fragments. Building on the established paradigm of radical-mediated protein damage, we propose that biradical species generated via cycloaromatization of enediynes destabilize the hydrophobic core of Aβ through either hydrogen abstraction from peptide or modification of its backbone. Furthermore, the elevate concentration of oxidation products leads to alterations in the local chemical environment, thereby facilitating hydrolysis of the peptide bonds. These findings highlight the potential of enediynes as chemically tractable tools for modulating Aβ aggregation and validate radical-based strategies for targeting amyloid species in neurodegenerative diseases.