%0 Journal Article
%A Sevenich, Marc
%A Gering, Ian
%A Kass, Bettina
%A Vollmer, Madita
%A Aghabashlou Saisan, Selma
%A Tusche, Markus
%A Kupreichyk, Tatsiana
%A Pauly, Thomas
%A Stoldt, Matthias
%A Hoyer, Wolfgang
%A Willuweit, Antje
%A Kutzsche, Janine
%A Lakomek, Nils-Alexander
%A Nagel-Steger, Luitgard
%A Gremer, Lothar
%A Tamgüney, Gültekin
%A Mohrlüder, Jeannine
%A Willbold, Dieter
%T Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide
%J npj Parkinson's Disease
%V 11
%N 1
%@ 2373-8057
%C [London]
%I Springer Nature
%M FZJ-2025-03861
%P 271
%D 2025
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ 40983605
%U <Go to ISI:>//WOS:001575814700001
%R 10.1038/s41531-025-01132-7
%U https://juser.fz-juelich.de/record/1046551