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Published on: March 27, 2017
Breaking Down the Core Peptide of Amyloid Beta Protein with Enediyne and Mechanistic Study
Meiling Tang1, Han Zhang2, Jiayi Shen2
1Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China.
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.
Insights
Enediyne derivatives disrupt amyloid-beta (Aβ) aggregates, a key feature of Alzheimer's disease. This radical-based strategy offers a novel approach to targeting neurodegenerative disease pathologies.
Area of Science:
- Biochemistry
- Neuroscience
- Medicinal Chemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) protein aggregation.
- Current AD therapies targeting Aβ synthesis/clearance have limited clinical efficacy.
- Directly disrupting Aβ aggregates is an unmet therapeutic need.
Purpose of the Study:
- To validate the peptide cleavage capability of enediyne derivatives against Aβ aggregates.
- To explore radical-based mechanisms for destabilizing Aβ.
- To assess enediynes as potential therapeutic agents for Alzheimer's disease.
Main Methods:
- Utilized a hydrogel model of Aβ core peptide.
- Employed enediyne derivatives to induce peptide cleavage.
- Analyzed cleavage fragments using high-resolution liquid chromatography-mass spectrometry.
Main Results:
- Enediyne derivatives successfully cleaved Aβ peptides in the hydrogel model.
- Radical species generated via enediyne cycloaromatization destabilized the Aβ hydrophobic core.
- Oxidation products facilitated peptide bond hydrolysis, altering the local chemical environment.
Conclusions:
- Enediynes demonstrate potential as chemically tractable tools for modulating Aβ aggregation.
- Radical-based strategies show promise for targeting amyloid species in neurodegenerative diseases.
- This study validates a novel mechanism for Aβ aggregate disruption.
