Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State

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Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State. / Kurnik, Martin; Sahin, Cagla; Andersen, Camilla Bertel; Lorenzen, Nikolai; Giehm, Lise; Mohammad-Beigi, Hossein; Jessen, Christian Moestrup; Pedersen, Jan Skov; Christiansen, Gunna; Petersen, Steen Vang; Staal, Roland; Krishnamurthy, Girija; Pitts, Keith; Reinhart, Peter H; Mulder, Frans A A; Mente, Scot; Hirst, Warren D; Otzen, Daniel E.

I: Cell Chemical Biology, Bind 25, Nr. 11, 15.11.2018, s. 1389-1402.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Kurnik, M, Sahin, C, Andersen, CB, Lorenzen, N, Giehm, L, Mohammad-Beigi, H, Jessen, CM, Pedersen, JS, Christiansen, G, Petersen, SV, Staal, R, Krishnamurthy, G, Pitts, K, Reinhart, PH, Mulder, FAA, Mente, S, Hirst, WD & Otzen, DE 2018, 'Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State', Cell Chemical Biology, bind 25, nr. 11, s. 1389-1402. https://doi.org/10.1016/j.chembiol.2018.08.005

APA

Kurnik, M., Sahin, C., Andersen, C. B., Lorenzen, N., Giehm, L., Mohammad-Beigi, H., Jessen, C. M., Pedersen, J. S., Christiansen, G., Petersen, S. V., Staal, R., Krishnamurthy, G., Pitts, K., Reinhart, P. H., Mulder, F. A. A., Mente, S., Hirst, W. D., & Otzen, D. E. (2018). Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State. Cell Chemical Biology, 25(11), 1389-1402. https://doi.org/10.1016/j.chembiol.2018.08.005

CBE

Kurnik M, Sahin C, Andersen CB, Lorenzen N, Giehm L, Mohammad-Beigi H, Jessen CM, Pedersen JS, Christiansen G, Petersen SV, Staal R, Krishnamurthy G, Pitts K, Reinhart PH, Mulder FAA, Mente S, Hirst WD, Otzen DE. 2018. Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State. Cell Chemical Biology. 25(11):1389-1402. https://doi.org/10.1016/j.chembiol.2018.08.005

MLA

Vancouver

Author

Kurnik, Martin ; Sahin, Cagla ; Andersen, Camilla Bertel ; Lorenzen, Nikolai ; Giehm, Lise ; Mohammad-Beigi, Hossein ; Jessen, Christian Moestrup ; Pedersen, Jan Skov ; Christiansen, Gunna ; Petersen, Steen Vang ; Staal, Roland ; Krishnamurthy, Girija ; Pitts, Keith ; Reinhart, Peter H ; Mulder, Frans A A ; Mente, Scot ; Hirst, Warren D ; Otzen, Daniel E. / Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State. I: Cell Chemical Biology. 2018 ; Bind 25, Nr. 11. s. 1389-1402.

Bibtex

@article{5db8c79791294ffc9d5099cacae6acc6,
title = "Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State",
abstract = "α-Synuclein (αSN) aggregation is central to the etiology of Parkinson's disease (PD). Large-scale screening of compounds to identify aggregation inhibitors is challenged by stochastic αSN aggregation and difficulties in detecting early-stage oligomers (αSOs). We developed a high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages in αSN aggregation. We screened 746,000 compounds, leading to 58 hits that markedly inhibit αSN aggregation and reduce αSOs' membrane permeabilization activity. The most effective aggregation inhibitors were derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide. They interacted strongly with the N-terminal part of monomeric αSN and reduced αSO-membrane interactions, possibly by affecting electrostatic interactions. Several compounds reduced αSO toxicity toward neuronal cell lines. The inhibitors introduced chemical modifications of αSN that were, however, not a prerequisite for inhibitory activity. We also identified several phenyl-benzoxazol compounds that promoted αSN aggregation (proaggregators). These compounds may be useful tools to modulate αSN aggregation in cellula.",
author = "Martin Kurnik and Cagla Sahin and Andersen, {Camilla Bertel} and Nikolai Lorenzen and Lise Giehm and Hossein Mohammad-Beigi and Jessen, {Christian Moestrup} and Pedersen, {Jan Skov} and Gunna Christiansen and Petersen, {Steen Vang} and Roland Staal and Girija Krishnamurthy and Keith Pitts and Reinhart, {Peter H} and Mulder, {Frans A A} and Scot Mente and Hirst, {Warren D} and Otzen, {Daniel E}",
note = "Copyright {\textcopyright} 2018 Elsevier Ltd. All rights reserved.",
year = "2018",
month = nov,
day = "15",
doi = "10.1016/j.chembiol.2018.08.005",
language = "English",
volume = "25",
pages = "1389--1402",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "11",

}

RIS

TY - JOUR

T1 - Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State

AU - Kurnik, Martin

AU - Sahin, Cagla

AU - Andersen, Camilla Bertel

AU - Lorenzen, Nikolai

AU - Giehm, Lise

AU - Mohammad-Beigi, Hossein

AU - Jessen, Christian Moestrup

AU - Pedersen, Jan Skov

AU - Christiansen, Gunna

AU - Petersen, Steen Vang

AU - Staal, Roland

AU - Krishnamurthy, Girija

AU - Pitts, Keith

AU - Reinhart, Peter H

AU - Mulder, Frans A A

AU - Mente, Scot

AU - Hirst, Warren D

AU - Otzen, Daniel E

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2018/11/15

Y1 - 2018/11/15

N2 - α-Synuclein (αSN) aggregation is central to the etiology of Parkinson's disease (PD). Large-scale screening of compounds to identify aggregation inhibitors is challenged by stochastic αSN aggregation and difficulties in detecting early-stage oligomers (αSOs). We developed a high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages in αSN aggregation. We screened 746,000 compounds, leading to 58 hits that markedly inhibit αSN aggregation and reduce αSOs' membrane permeabilization activity. The most effective aggregation inhibitors were derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide. They interacted strongly with the N-terminal part of monomeric αSN and reduced αSO-membrane interactions, possibly by affecting electrostatic interactions. Several compounds reduced αSO toxicity toward neuronal cell lines. The inhibitors introduced chemical modifications of αSN that were, however, not a prerequisite for inhibitory activity. We also identified several phenyl-benzoxazol compounds that promoted αSN aggregation (proaggregators). These compounds may be useful tools to modulate αSN aggregation in cellula.

AB - α-Synuclein (αSN) aggregation is central to the etiology of Parkinson's disease (PD). Large-scale screening of compounds to identify aggregation inhibitors is challenged by stochastic αSN aggregation and difficulties in detecting early-stage oligomers (αSOs). We developed a high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages in αSN aggregation. We screened 746,000 compounds, leading to 58 hits that markedly inhibit αSN aggregation and reduce αSOs' membrane permeabilization activity. The most effective aggregation inhibitors were derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide. They interacted strongly with the N-terminal part of monomeric αSN and reduced αSO-membrane interactions, possibly by affecting electrostatic interactions. Several compounds reduced αSO toxicity toward neuronal cell lines. The inhibitors introduced chemical modifications of αSN that were, however, not a prerequisite for inhibitory activity. We also identified several phenyl-benzoxazol compounds that promoted αSN aggregation (proaggregators). These compounds may be useful tools to modulate αSN aggregation in cellula.

U2 - 10.1016/j.chembiol.2018.08.005

DO - 10.1016/j.chembiol.2018.08.005

M3 - Journal article

C2 - 30197194

VL - 25

SP - 1389

EP - 1402

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9456

IS - 11

ER -