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001046551 1001_ $$0P:(DE-Juel1)165152$$aSevenich, Marc$$b0
001046551 245__ $$aDirect disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide
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001046551 520__ $$aA hallmark of Parkinson's disease (PD) is the progressive neurodegeneration associated with soluble oligomeric and fibrillar forms of misfolded α-synuclein (α-syn). In this study, all-D-enantiomeric peptide ligands are presented that bind monomeric α-syn with high affinity, stabilize its physiological monomeric status, prevent aggregation and dissolve existing aggregates. This "antiprionic" mode of action directly targets pathogenic aggregated particles. Using mirror-image phage display on D-enantiomeric full-length α-syn, SVD-1 and SVD-1a were identified, showing a delay of aggregation and reduction of aggregate formation in both de novo and seeded models. Picomolar KDs were confirmed by SPR, where a highly dynamic interaction mode was verified by PRE-NMR. SVD-1a also reduced the toxicity and intracellular seeding of α-syn fibrils in cell culture by disassembling them into monomers, as confirmed by atomic force microscopy and dynamic light scattering. These results support SVD-1a as a promising lead compound for the treatment of Parkinson's disease.
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001046551 7001_ $$0P:(DE-Juel1)171922$$aGering, Ian$$b1
001046551 7001_ $$0P:(DE-Juel1)171532$$aKass, Bettina$$b2
001046551 7001_ $$0P:(DE-HGF)0$$aVollmer, Madita$$b3
001046551 7001_ $$0P:(DE-Juel1)190277$$aAghabashlou Saisan, Selma$$b4
001046551 7001_ $$0P:(DE-Juel1)131709$$aTusche, Markus$$b5
001046551 7001_ $$0P:(DE-Juel1)176456$$aKupreichyk, Tatsiana$$b6
001046551 7001_ $$0P:(DE-Juel1)184822$$aPauly, Thomas$$b7
001046551 7001_ $$0P:(DE-Juel1)132023$$aStoldt, Matthias$$b8
001046551 7001_ $$0P:(DE-Juel1)201143$$aHoyer, Wolfgang$$b9$$ufzj
001046551 7001_ $$0P:(DE-Juel1)144347$$aWilluweit, Antje$$b10
001046551 7001_ $$0P:(DE-Juel1)159137$$aKutzsche, Janine$$b11
001046551 7001_ $$0P:(DE-Juel1)180657$$aLakomek, Nils-Alexander$$b12
001046551 7001_ $$0P:(DE-Juel1)162443$$aNagel-Steger, Luitgard$$b13
001046551 7001_ $$0P:(DE-Juel1)145165$$aGremer, Lothar$$b14
001046551 7001_ $$0P:(DE-Juel1)177986$$aTamgüney, Gültekin$$b15
001046551 7001_ $$0P:(DE-Juel1)132012$$aMohrlüder, Jeannine$$b16$$eCorresponding author
001046551 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b17$$eCorresponding author
001046551 773__ $$0PERI:(DE-600)2819218-7$$a10.1038/s41531-025-01132-7$$gVol. 11, no. 1, p. 271$$n1$$p271$$tnpj Parkinson's Disease$$v11$$x2373-8057$$y2025
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