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

Antonschmidt, Leif; Matthes, Dirk; Dervisoglu, Riza; Frieg, Benedikt; Dienemann, Christian; Leonov, Andrei; Nimerovsky, Evgeny; Sant, Vrinda; Ryazanov, Sergey; Giese, Armin; Schroeder, Gunnar F.; Becker, Stefan; de Groot, Bert L.; Griesinger, Christian and Andreas, Loren B. (2022): The clinical drug candidate anle138b binds in a cavity of lipidic alpha-synuclein fibrils. In: Nature Communications, Vol. 13, No. 1, 5385

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 alpha-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 alpha-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two beta-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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390729940
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 397022504