TY  - JOUR
AU  - Han, Mookyoung
AU  - Frieg, Benedikt
AU  - Matthes, Dirk
AU  - Leonov, Andrei
AU  - Ryazanov, Sergey
AU  - Giller, Karin
AU  - Nimerovsky, Evgeny
AU  - Stampolaki, Marianna
AU  - Xue, Kai
AU  - Overkamp, Kerstin
AU  - Dienemann, Christian
AU  - Riedel, Dietmar
AU  - Giese, Armin
AU  - Becker, Stefan
AU  - de Groot, Bert L.
AU  - Schröder, Gunnar F.
AU  - Andreas, Loren B.
AU  - Griesinger, Christian
TI  - Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - FZJ-2025-04506
SP  - 8850
PY  - 2025
AB  - 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 andmay inform the development of therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. Thismay suggest amechanistic connection to its previously reported activity in animal models of Alzheimer’s disease.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s41467-025-64443-6
UR  - https://juser.fz-juelich.de/record/1048115
ER  -