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Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates.

ABSTRACT: The presence of amyloid fibrils of α-synuclein is closely associated with Parkinson's disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a range of kinetic and thermodynamic assays for their ability to bind α-synuclein fibrils and prevent the further generation of α-synuclein oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of α-synuclein aggregates.

SUBMITTER: Chia S

PROVIDER: S-EPMC9811465 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates.

Chia Sean S Faidon Brotzakis Z Z Horne Robert I RI Possenti Andrea A Mannini Benedetta B Cataldi Rodrigo R Nowinska Magdalena M Staats Roxine R Linse Sara S Knowles Tuomas P J TPJ Habchi Johnny J Vendruscolo Michele M

Molecular pharmaceutics 20221114 1

The presence of amyloid fibrils of α-synuclein is closely associated with Parkinson's disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The r ...[more]

PMID: 36374974

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Project description:Tau and α-synuclein aggregates are the main histopathological hallmarks present in Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders. Intraneuronal hyperphosphorylated tau accumulation is significantly connected to the degree of cognitive impairment in AD patients. In particular, the longest 2N4R tau isoform has a propensity to rapidly form oligomers and mature fibrils. On the other hand, misfolding of α-synuclein (α-syn) is the characteristic feature in PD and dementia with Lewy bodies (DLB). There is a strong crosstalk between the two prone-to-aggregation proteins as they coprecipitated in some brains of AD, PD, and DLB patients. Simultaneous targeting of both proteinaceous oligomers and aggregates is still challenging. Here, we rationally designed and synthesized benzothiazole- and indole-based compounds using the structural hybridization strategy between the benzothiazole N744 cyanine dye and the diphenyl pyrazole Anle138b that showed anti-aggregation activity towards 2N4R tau and α-syn, respectively. The anti-aggregation effect of the prepared compounds was monitored using the thioflavin-T (ThT) fluorescence assay, while transmission electron microscopy (TEM) was employed to detect fibrils upon the completion of a time-course study with the ThT assay. Moreover, the photo-induced crosslinking of unmodified protein (PICUP) assay was used to determine the formation of oligomers. Specifically, compounds 46 and 48 demonstrated the highest anti-aggregation activity by decreasing the ThT fluorescence to 4.0 and 14.8%, respectively, against α-syn. Although no noticeable effect on 2N4R tau oligomers, 46 showed promising anti-oligomer activity against α-syn. Both compounds induced a significantly high anti-aggregation effect against the two protein fibrils as visualized by TEM. Moreover, compound 48 remarkably inhibited α-syn inclusion and cell confluence using M17D cells. Collectively, compounds 46 and 48 could serve as a basic structure for further optimization to develop clinically active AD and PD disease-modifying agents.

Project description:BackgroundParkinson's disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson's disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies.MethodsTo identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models.ResultsWe found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson's disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model.ConclusionsWe identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson's disease.

Dataset Information

Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates.

Publications

Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates.

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