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The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation

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Titel: The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation
Autoren: Mookyoung Han, Benedikt Frieg, Dirk Matthes, Andrei Leonov, Sergey Ryazanov, Karin Giller, Evgeny Nimerovsky, Marianna Stampolaki, Kai Xue, Kerstin Overkamp, Christian Dienemann, Dietmar Riedel, Armin Giese, Stefan Becker, Bert L. de Groot, Gunnar F. Schröder, Loren B. Andreas, Christian Griesinger
Weitere Verfasser: Han, Mookyoung, Frieg, Benedikt, Matthes, Dirk, Leonov, Andrei, Ryazanov, Sergey, Giller, Karin, Nimerovsky, Evgeny, Stampolaki, Marianna, Xue, Kai, Overkamp, Kerstin, Dienemann, Christian, Riedel, Dietmar, Giese, Armin, Becker, Stefan, de Groot, Bert L., Schröder, Gunnar F., Andreas, Loren B., Griesinger, Christian
Publication Status: Preprint
Verlagsinformationen: Springer Science and Business Media LLC, 2025.
Publikationsjahr: 2025
Beschreibung: Alzheimer’s disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic Aβ₄₀ fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimer’s patients¹⁸. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of novel therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimer’s disease¹⁵.
Publikationsart: Article
DOI: 10.21203/rs.3.rs-6770178/v1
DOI: 10.1101/2025.05.30.655790
Zugangs-URL: https://resolver.sub.uni-goettingen.de/purl?gro-2/151223
Rights: CC BY
Dokumentencode: edsair.doi.dedup.....9a44b35f252c6a656ee5adead9e265e0
Datenbank: OpenAIRE
Beschreibung
Abstract:Alzheimer’s disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic Aβ₄₀ fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimer’s patients¹⁸. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of novel therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimer’s disease¹⁵.
DOI:10.21203/rs.3.rs-6770178/v1