Objective: Development of high-affinity ligands to α-synuclein (α-syn) for a therapeutic approach aiming for the disassembly of α-syn aggregates as a disease-modifying treatment of synucleinopathies.
Background: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder worldwide and the most prevalent α-synucleinopathy. Multiple lines of evidence indicate that oligomeric α-syn assemblies play a key role in prion-like cell-to-cell transmission and induction of toxicity, leading to neurodegeneration in PD. Consequently, disassembly of these prion-like aggregates into physiological α-syn monomers is a very efficient way to interfere with disease progression in PD and other synucleinopathies.
Method: We have performed a mirror-image phage display against full-length α-syn and selected all-D-enantiomeric peptide ligands by means of of next generation sequencing. The efficacy of the compounds was characterized usingsurface plasmon resonance, atomic forced microscopy (AFM), dynamic light scattering (DLS), size exclusion chromatography (SEC), paramagnetic relaxation enhancement, nuclear magnetic resonance (NMR) spectroscopy, Thioflavin-T aggregation assay, cell-viability and cellular aggregation assays.
Results: We identified two lead compounds, SVD-1 and SVD-1a, which inhibited de novo and seeded α-syn aggregation very efficiently. Both showed high affinity to α-syn in the picomolar KD range and the interaction with α-syn was further characterized by NMR analyses. SVD-1a reduced toxic effects and intracellular seeding capacity of preformed α-syn oligomers in cell culture. Furthermore, we can show the compound´s ability to specifically disassemble α-syn oligomers into monomers as demonstrated by AFM, time dependent DLS and SEC analyses.
Conclusion: The present work reports on a promising lead compound capable of destabilizing and disassembling α-syn aggregates as a new disease-modifying treatment strategy against Parkinson’s disease and other synucleinopathies.
This abstract has been submitted to the AD/PD 2023 conference and will be presented on 03/31/2023.
To cite this abstract in AMA style:A. Willuweit, M. Sevenich, G. Tamgüney, J. Mohrlüder, D. Willbold. Development of therapeutic substances for the disassembly of α-synuclein aggregates as disease-modifying treatment of synucleinopathies [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/development-of-therapeutic-substances-for-the-disassembly-of-%ce%b1-synuclein-aggregates-as-disease-modifying-treatment-of-synucleinopathies/. Accessed September 22, 2023.
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