Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide

A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration associated with soluble oligomeric and fibrillar forms of misfolded α-synuclein (α-syn). In this study, all-D-enantiomeric peptide ligands are presented that bind monomeric α-syn with high affinity, stabilize its physiological monomeric status, prevent aggregation and dissolve existing aggregates. This "antiprionic" mode of action directly targets pathogenic aggregated particles. Using mirror-image phage display on D-enantiomeric full-length α-syn, SVD-1 and SVD-1a were identified, showing a delay of aggregation and reduction of aggregate formation in both de novo and seeded models. Picomolar KDs were confirmed by SPR, where a highly dynamic interaction mode was verified by PRE-NMR. SVD-1a also reduced the toxicity and intracellular seeding of α-syn fibrils in cell culture by disassembling them into monomers, as confirmed by atomic force microscopy and dynamic light scattering. These results support SVD-1a as a promising lead compound for the treatment of Parkinson's disease.

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Publication Details

Journal
npj Parkinson s Disease
Published
2025-09-22
DOI
https://doi.org/10.1038/s41531-025-01132-7
Primary Topic
Chemical Synthesis and Analysis
Type
article
Field-Weighted Citation Impact
0.00

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article

Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide

Tatsiana Kupreichyk, Bettina Kass, Madita Vollmer, Ian Gering et al.
npj Parkinson s Disease
Chemical Synthesis and Analysis
article

Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide

Tatsiana Kupreichyk, Bettina Kass, Madita Vollmer, Ian Gering, Antje Willuweit, Selma Aghabashlou Saisan, Markus Tusche, Marc Sevenich, Thomas Pauly, Nils‐Alexander Lakomek, Gültekin Tamgüney, Luitgard Nagel‐Steger, Lothar Gremer, Jeannine Mohrlüder, Matthias Stoldt, Wolfgang Hoyer, Janine Kutzsche, Dieter Willbold
article en

Abstract

A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration associated with soluble oligomeric and fibrillar forms of misfolded α-synuclein (α-syn). In this study, all-D-enantiomeric peptide ligands are presented that bind monomeric α-syn with high affinity, stabilize its physiological monomeric status, prevent aggregation and dissolve existing aggregates. This "antiprionic" mode of action directly targets pathogenic aggregated particles. Using mirror-image phage display on D-enantiomeric full-length α-syn, SVD-1 and SVD-1a were identified, showing a delay of aggregation and reduction of aggregate formation in both de novo and seeded models. Picomolar KDs were confirmed by SPR, where a highly dynamic interaction mode was verified by PRE-NMR. SVD-1a also reduced the toxicity and intracellular seeding of α-syn fibrils in cell culture by disassembling them into monomers, as confirmed by atomic force microscopy and dynamic light scattering. These results support SVD-1a as a promising lead compound for the treatment of Parkinson's disease.

npj Parkinson s DiseaseVol. 11(1)
Forschungszentrum Jülich (DE), Heinrich Heine University Düsseldorf (DE), Hochschule Düsseldorf University of Applied Sciences (DE)
Michael J. Fox Foundation for Parkinson's Research, Forschungszentrum Jülich
Openalex Percentile: Top 77%
Chemical Synthesis and Analysis
DOIOpen Access PDFOpenAlex
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