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@ARTICLE{Han:1048115,
author = {Han, Mookyoung and Frieg, Benedikt and Matthes, Dirk and
Leonov, Andrei and Ryazanov, Sergey and Giller, Karin and
Nimerovsky, Evgeny and Stampolaki, Marianna and Xue, Kai and
Overkamp, Kerstin and Dienemann, Christian and Riedel,
Dietmar and Giese, Armin and Becker, Stefan and de Groot,
Bert L. and Schröder, Gunnar F. and Andreas, Loren B. and
Griesinger, Christian},
title = {{A}nle138b binds predominantly to the central cavity in
lipidic {A}β₄₀ fibrils and modulates fibril formation},
journal = {Nature Communications},
volume = {16},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {FZJ-2025-04506},
pages = {8850},
year = {2025},
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 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.},
cin = {IBI-7},
ddc = {500},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5244 - Information Processing in Neuronal Networks
(POF4-524)},
pid = {G:(DE-HGF)POF4-5244},
typ = {PUB:(DE-HGF)16},
doi = {10.1038/s41467-025-64443-6},
url = {https://juser.fz-juelich.de/record/1048115},
}