ArticleScientific reports2019
Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Targeting protein disorder: the next hurdle in drug discovery.Nature reviews. Drug discovery · 2025Review
- Neurodegeneration models in Parkinson's disease: cellular and molecular paths to neuron death.Behavioral and brain functions : BBF · 2025Review
- Nanoplatforms Targeting Intrinsically Disordered Protein Aggregation for Translational Neuroscience Applications.Nanomaterials (Basel, Switzerland) · 2025Review
- pH Effects Can Dominate Chemical Shift Perturbations inACS chemical neuroscience · 2023Article
- Controlling amyloid formation of intrinsically disordered proteins and peptides: slowing down or speeding up?Essays in biochemistry · 2022Article
- Chemical tools for study and modulation of biomolecular phase transitions.Chemical science · 2022Review
- 3,4-Dihydroxyphenylethanol and 3,4-dihydroxyphenylacetic acid affect the aggregation process of E46K variant of α-synuclein at different extent: Insights into the interplay between protein dynamics and catechol effect.Protein science : a publication of the Protein Society · 2022Article
- α-synuclein enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis.Journal of proteins and proteomics · 2022Article
- α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword.Biomolecules · 2022Review
- Low dose DMSO treatment induces oligomerization and accelerates aggregation of α-synuclein.Scientific reports · 2022Article
- One ring is sufficient to inhibit α-synuclein aggregation.Neural regeneration research · 2022Review
- The dopamine receptor agonist apomorphine stabilizes neurotoxic α-synuclein oligomers.FEBS letters · 2022Article
- DisProt in 2022: improved quality and accessibility of protein intrinsic disorder annotation.Nucleic acids research · 2022Article
- Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm.Frontiers in bioengineering and biotechnology · 2020Article
- Intracellular Alpha-Synuclein and Immune Cell Function.Frontiers in cell and developmental biology · 2020Review
- Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism.The Journal of biological chemistryArticle
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Authors and funding
30 authors at 10 institutions in 7 countries.
Funding
Abstract
The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.