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  Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease.

Wagner, J., Ryazanov, S., Leonov, A., Levin, J., Shi, S., Schmidt, F., et al. (2013). Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathologica, 125(6), 795-813. doi:10.1007/s00401-013-1114-9.

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 Urheber:
Wagner, J., Autor
Ryazanov, S.1, Autor           
Leonov, A.1, Autor           
Levin, J., Autor
Shi, S., Autor
Schmidt, F., Autor
Prix, C., Autor
Pan-Montojo, F., Autor
Bertsch, U., Autor
Mitteregger-Kretzschmar, G., Autor
Geissen, M., Autor
Eiden, M., Autor
Leidel, F., Autor
Hirschberger, T., Autor
Deeg, A. A., Autor
Krauth, J., Autor
Zinth, W., Autor
Tavan, P., Autor
Pilger, J.1, Autor           
Zweckstetter, M.2, Autor           
Frank, T., AutorBaehr, M., AutorWeishaupt, J. H., AutorUhr, M., AutorUrlaub, H.3, Autor           Teichmann, U.4, Autor           Samwer, M., AutorBötzel, K., AutorGroschup, M., AutorKretzschmar, H., AutorGriesinger, C.1, Autor                 Giese, A., Autor mehr..
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              
3Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              
4Department of Molecular Cell Biology, MPI for biophysical chemistry, Max Planck Society, ou_578585              

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 Zusammenfassung: In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of alpha-synuclein (alpha-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and alpha-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.

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Sprache(n): eng - English
 Datum: 2013-04-192013-06
 Publikationsstatus: Erschienen
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 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1007/s00401-013-1114-9
 Art des Abschluß: -

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Titel: Acta Neuropathologica
Genre der Quelle: Zeitschrift
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Seiten: - Band / Heft: 125 (6) Artikelnummer: - Start- / Endseite: 795 - 813 Identifikator: -