Objective: Stabilization of monomeric α-synuclein protein (αSyn) by transient and high-affinity binding ligands is a novel and highly innovative anti-prionic treatment strategy for synucleinopathies .
Background: The most prevalent α-synucleinopathy is Parkinson’s disease (PD). More and more in vitro and in vivo data suggest that toxic αSyn assemblies behave prion-like. The presence of self-replicating and propagating etiologic agents in the brains of diseased patients has dramatic consequences for therapy development. Very importantly, the non-toxic and functional αSyn monomer is chemically 100% identical to the building blocks in toxic αSyn oligomers and fibrils. The only difference is their three-dimensional conformation. αSyn monomers are intrinsically disordered proteins (IDPs) without defined rigid conformation. The same protein molecule in oligomer assemblies and fibrils does have a highly defined conformation that is even able to recruit monomers in order to grow and replicate. Identification of ligands that stabilize αSyn monomers in their native IDP-like conformation is not a trivial or very intuitive, but possibly the most successful, strategy for the development of drugs that directly disassemble toxic oligomers into their native and functional monomer building blocks.
Method: We have identified all-D-peptides by mirror-image phage display against monomeric full-length αSyn that were further analyzed for their effect on αSyn aggregation kinetics using Thioflavin-T (ThT) analysis, fluorescence microscopy and atomic force microscopy (AFM). The binding kinetics were analyzed using surface plasmon resonance (SPR) and microthermophoresis. αSyn oligomer elimination efficacy was measured by an αSyn-QIAD assay.
Results: We have identified several all-D-peptides, which interfered with αSyn aggregation kinetics. One candidate (SVD-1) showed an exceptionally strong impact during the ThT-experiments. It inhibited αSyn fibril formation and strongly bound to the monomeric form of αSyn.
Conclusion: SFD-1 seems to be a promising lead candidate for a potential therapeutic approach, which aims at the destabilization and disassembly of toxic αSyn assemblies into functional monomers. We will also report on the properties of the optimized leads.
To cite this abstract in AMA style:
D. Willbold, M. Sevenich, W. Hoyer, J. Mohrlüder, A. Willuweit. Identification and characterization of anti-prionic compounds that disassemble αSyn prions as a novel therapeutic approach for synucleinopathies [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/identification-and-characterization-of-anti-prionic-compounds-that-disassemble-%ce%b1syn-prions-as-a-novel-therapeutic-approach-for-synucleinopathies/. Accessed November 24, 2024.« Back to MDS Virtual Congress 2020
MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-and-characterization-of-anti-prionic-compounds-that-disassemble-%ce%b1syn-prions-as-a-novel-therapeutic-approach-for-synucleinopathies/