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

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.

Alpha Synuclein: Neurodegeneration and Inflammation

“…These include anle138b, a lead compound from a systematic high-throughput screening test combined with medicinal chemistry optimization, which showed anti-oligomerization activity against prion and α-Syn aggregates [ 204 ]. The intimate mechanism of interaction of anle138b with α-Syn fibrils has been investigated with cryo-EM, revealing stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils [ 205 ]. In different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo [ 204 , 206 , 207 ] and motor deficits in MSA models [ 208 , 209 , 210 ].…”

PET imaging in animal models of Parkinson’s disease

“…Future perspective: One of the unmet need in PD imaging is the development of specific αSyn tracer. Recent studies using nuclear magnetic resonance method enable to model the binding site of ligand on αSyn fibrils with higher precision in addition to the in silico modeling approach [159]. Recent advances in electron cryo-microscopy (cryo-EM) analysis of αSyn structures from brain of patients with Lewy pathology [157] and MSA [158] provide new opportunity for rationalized design of αSyn imaging tracers with better binding specificity and high accuracy characterization tool.…”

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

“…The interaction with oligomeric α-Syn precludes the formation of β-sheet interactions, thus avoiding further amyloid aggregation. A recent structural analysis (including CryoEM, solid-state NMR, and solution NMR) has evinced that anle138b binds into the inner cavity of the lipidic fibrillar structure by interacting with Ile188, G68, and G86 [ 327 ]. This interaction, driven by polar contacts, causes local structural modifications, altering the structural fluctuations of residues close to the inner cavity [ 327 ].…”

“…A recent structural analysis (including CryoEM, solid-state NMR, and solution NMR) has evinced that anle138b binds into the inner cavity of the lipidic fibrillar structure by interacting with Ile188, G68, and G86 [ 327 ]. This interaction, driven by polar contacts, causes local structural modifications, altering the structural fluctuations of residues close to the inner cavity [ 327 ]. The oral administration of anle138b in three different mice models of PD ameliorated PD-related symptoms such as motor activity, gut motility, neuroprotection, and survival [ 323 , 328 ].…”