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

Nature communications 2022 Sep 14

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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. © 2022. The Author(s).

Citation

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 de Groot, Christian Griesinger, Loren B Andreas. The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils. Nature communications. 2022 Sep 14;13(1):5385