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<p>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-<span>d</span>-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 <span>d</span>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月22日

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

摘要

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.