The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils

Leif Antonschmidt, Dirk Matthes, Rıza Dervişoğlu, Benedikt Frieg, Christian Dienemann, Andrei Leonov, Evgeny Nimerovsky, Vrinda Sant, Sergey Ryazanov, Armin Giese, Gunnar F. Schröder, Stefan Becker, Bert L. Groot (), Christian Griesinger () and Loren B. Andreas ()
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Leif Antonschmidt: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Dirk Matthes: Max Planck Institute for Multidisciplinary Sciences
Rıza Dervişoğlu: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Benedikt Frieg: Forschungszentrum Jülich
Christian Dienemann: Max Planck Institute for Multidisciplinary Sciences
Andrei Leonov: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Evgeny Nimerovsky: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Vrinda Sant: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Sergey Ryazanov: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Armin Giese: MODAG GmbH
Gunnar F. Schröder: Forschungszentrum Jülich
Stefan Becker: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Bert L. Groot: Max Planck Institute for Multidisciplinary Sciences
Christian Griesinger: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences
Loren B. Andreas: NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well.

Date: 2022
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DOI: 10.1038/s41467-022-32797-w

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