ArticleNPJ Parkinson's disease2021
Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.
Article in NPJ Parkinson's disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- A Live-Cell Imaging System for the Identification of Pro- and Anti-Aggregatory α-Synuclein Modulators.Molecular neurobiology · 2026Article
- Molecular profiling of alpha-synuclein pathology and seeding activity in Parkinson's disease.Acta neuropathologica · 2026Article
- Article
- Nanoplasmonic Infrared Microarray Sensor Enabling Structural Protein Biomarker-Based Drug Screening for Neurodegenerative Diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Micro- and nanoscale biosensing technologies for early diagnosis of Parkinson's disease.Mikrochimica acta · 2025Review
- Fluorescence Lifetime-Based FRET Biosensors for Monitoring N Terminal Domain-Dependent Interactions of TDP-43 in Living Cells: A Novel Approach for ALS and FTD Drug Discovery.ACS chemical neuroscience · 2025Article
- Multiplexed Dark FRET Biosensors: An accessible live-cell platform for target- and cell-specific monitoring of protein-protein interactions in 2D and 3D model systems.Research square · 2025Article
- Nanoplatforms Targeting Intrinsically Disordered Protein Aggregation for Translational Neuroscience Applications.Nanomaterials (Basel, Switzerland) · 2025Review
- Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.Pharmaceutics · 2023Review
- HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin.SLAS discovery : advancing life sciences R & D · 2023Article
- Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson's Disease.Pharmaceutics · 2023Review
- Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives.Antioxidants (Basel, Switzerland) · 2023Article
- pH Effects Can Dominate Chemical Shift Perturbations inACS chemical neuroscience · 2023Article
- Alpha synuclein post translational modifications: potential targets for Parkinson's disease therapy?Frontiers in molecular neuroscience · 2023Review
- In Silico Study of the Interactions of Anle138b Isomer, an Inhibitor of Amyloid Aggregation, with Partner Proteins.International journal of molecular sciences · 2022Article
- Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry.ACS infectious diseases · 2022Article
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- Article
- Challenges in Discovering Drugs That Target the Protein-Protein Interactions of Disordered Proteins.International journal of molecular sciences · 2022Review
- Non-monotonic fibril surface occlusion by GFP tags from coarse-grained molecular simulations.Computational and structural biotechnology journal · 2022Article
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
We have developed a high-throughput drug discovery platform, measuring fluorescence resonance energy transfer (FRET) with fluorescent alpha-synuclein (αSN) biosensors, to detect spontaneous pre-fibrillar oligomers in living cells. Our two αSN FRET biosensors provide complementary insight into αSN oligomerization and conformation in order to improve the success of drug discovery campaigns for the treatment of Parkinson's disease. We measure FRET by fluorescence lifetime, rather than traditional fluorescence intensity, providing a structural readout with greater resolution and precision. This facilitates identification of compounds that cause subtle but significant conformational changes in the ensemble of oligomeric states that are easily missed using intensity-based FRET. We screened a 1280-compound small-molecule library and identified 21 compounds that changed the lifetime by >5 SD. Two of these compounds have nanomolar potency in protecting SH-SY5Y cells from αSN-induced death, providing a nearly tenfold improvement over known inhibitors. We tested the efficacy of several compounds in a primary mouse neuron assay of αSN pathology (phosphorylation of mouse αSN pre-formed fibrils) and show rescue of pathology for two of them. These hits were further characterized with biophysical and biochemical assays to explore potential mechanisms of action. In vitro αSN oligomerization, single-molecule FRET, and protein-observed fluorine NMR experiments demonstrate that these compounds modulate αSN oligomers but not monomers. Subsequent aggregation assays further show that these compounds also deter or block αSN fibril assembly.
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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.