TY  - JOUR
AU  - Sevenich, Marc
AU  - Gering, Ian
AU  - Kass, Bettina
AU  - Vollmer, Madita
AU  - Aghabashlou Saisan, Selma
AU  - Tusche, Markus
AU  - Kupreichyk, Tatsiana
AU  - Pauly, Thomas
AU  - Stoldt, Matthias
AU  - Hoyer, Wolfgang
AU  - Willuweit, Antje
AU  - Kutzsche, Janine
AU  - Lakomek, Nils-Alexander
AU  - Nagel-Steger, Luitgard
AU  - Gremer, Lothar
AU  - Tamgüney, Gültekin
AU  - Mohrlüder, Jeannine
AU  - Willbold, Dieter
TI  - Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide
JO  - npj Parkinson's Disease
VL  - 11
IS  - 1
SN  - 2373-8057
CY  - [London]
PB  - Springer Nature
M1  - FZJ-2025-03861
SP  - 271
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 40983605
UR  - <Go to ISI:>//WOS:001575814700001
DO  - DOI:10.1038/s41531-025-01132-7
UR  - https://juser.fz-juelich.de/record/1046551
ER  -