In EDS ansehen

Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation

Gespeichert in:
Bibliographische Detailangaben
Titel: 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
Quelle: Nature Communications, Vol 16, Iss 1, Pp 1-17 (2025)
Verlagsinformationen: Nature Portfolio, 2025.
Publikationsjahr: 2025
Bestand: LCC:Science
Schlagwörter: Science
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 patients. 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 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 disease.
Publikationsart: article
Dateibeschreibung: electronic resource
Sprache: English
ISSN: 2041-1723
Relation: https://doaj.org/toc/2041-1723
DOI: 10.1038/s41467-025-64443-6
Zugangs-URL: https://doaj.org/article/66dca204928549c2bfdef2e49e8cc368
Dokumentencode: edsdoj.66dca204928549c2bfdef2e49e8cc368
Datenbank: Directory of Open Access Journals
Beschreibung
Abstract: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 patients. 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 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 disease.
ISSN:20411723
DOI:10.1038/s41467-025-64443-6