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

• Published in: Nature communications 2022-09, Vol.13 (1), p.5385-10, Article 5385
• Main Authors: Antonschmidt, Leif, Matthes, Dirk, Dervişoğlu, Rıza, Frieg, Benedikt, Dienemann, Christian, Leonov, Andrei, Nimerovsky, Evgeny, Sant, Vrinda, Ryazanov, Sergey, Giese, Armin, Schröder, Gunnar F., Becker, Stefan, de Groot, Bert L., Griesinger, Christian, Andreas, Loren B.
• Format: Article
• Language: English
• Subjects: 101/6; 631/378/340; 631/535/1267; 631/535/878/1264; 631/92/470/2284; Aggregates; alpha-Synuclein - metabolism; Amyloidogenesis; Benzodioxoles - chemistry; Binding sites; Drug development; Electron microscopy; Fibrils; Holes; Humanities and Social Sciences; Lipids; Magnetic resonance spectroscopy; Molecular dynamics; Movement disorders; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; NMR; NMR spectroscopy; Nuclear magnetic resonance; Parkinson's disease; Positron emission; Positron emission tomography; Protein Aggregates; Proteins; Pyrazoles - chemistry; Science; Science (multidisciplinary); Synuclein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32797-w

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. Understanding how small molecules bind to pathological aggregates is of importance for therapeutic and diagnostic development in diseases such as Parkinson’s Disease. Here, the authors reveal a binding site of anle138b to lipid-induced α-synuclein fibrils.