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Authors
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Firdaus, S.; Boye, S.; Janke, A.; Friedel, P.; Janaszewska, A.; Appelhans, D.; Müller, M.; Klajnert-Maculewicz, B.; Voit, B.; Lederer, A.
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Title
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Advancing Antiamyloidogenic Activity by Fine-Tuning Macromolecular Topology
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Date
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08.11.2023
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Number
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0
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Abstract
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Amyloid β peptide can aggregate into thin β-sheet fibrils or plaques deposited on the extracellular matrix, which is the hallmark of Alzheimer’s disease. Multifunctional macromolecular structures play an important role in inhibiting the aggregate formation of amyloidogenic materials and thus are promising candidates with antiamyloidogenic characteristics for the development of next-generation therapeutics. In this study, we evaluate how small differences in the dendritic topology of these structures influence their antiamyloidogenic activity by the comparison of “perfectly dendritic” and “pseudodendritic” macromolecules, both decorated with mannose units. Their compactness, the position of surface units, and the size of glyco-architectures influence their antiamyloidogenic activity against Aβ 40, a major component of amyloid plaques. For the advanced analysis of the aggregation of the Aβ peptide, we introduce asymmetric flow field flow fractionation as a suitable method for the quantification of large and delicate structures. This alternative method focuses on the quantification of complex aggregates of Aβ 40 and glycodendrimer/glyco-pseudodendrimer over different time intervals of incubation, showing a good correlation to ThT assay and CD spectroscopy results. Kinetic studies of the second-generation glyco-pseudodendrimer revealed maximum inhibition of Aβ 40 aggregates, verified with atomic force microscopy. The second-generation glyco-pseudodendrimer shows the best antiamyloidogenic properties confirming that macromolecular conformation in combination with optimal functional group distribution is the key to its performance. These molecular properties were validated and confirmed by molecular dynamics simulation.
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Publisher
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Wikidata
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Citation
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Biomacromolecules 24 (2023) 5797-5806
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DOI
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https://doi.org/10.1021/acs.biomac.3c00817
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Tags
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