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

Martin Kurnik; Cagla Sahin; Camilla Bertel Andersen; Nikolai Lorenzen; Lise Giehm; Hossein Mohammad-Beigi; Christian Moestrup Jessen; Jan Skov Pedersen; Gunna Christiansen; Steen Vang Petersen; Roland Staal; Girija Krishnamurthy; Keith Pitts; Peter H Reinhart; Frans A A Mulder; Scot Mente; Warren D Hirst; Daniel E Otzen

doi:10.1016/j.chembiol.2018.08.005

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

Martin Kurnik, Cagla Sahin, Camilla Bertel Andersen, Nikolai Lorenzen, Lise Giehm, Hossein Mohammad-Beigi, Christian Moestrup Jessen, Jan Skov Pedersen, Gunna Christiansen, Steen Vang Petersen, Roland Staal, Girija Krishnamurthy, Keith Pitts, Peter H Reinhart, Frans A A Mulder, Scot Mente, Warren D Hirst, Daniel E Otzen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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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. Kurnik et al. developed an FRET-based high-throughput screen for inhibitors of α-synuclein aggregation, critical in development of Parkinson's disease. Out of 746,000 compounds, the 6 best hits are derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide, interact with α-synuclein's N-region and reduce oligomer-membrane interactions. We also identified compounds promoting aggregation; the 2 best share a phenyl-benzoxazol core.

Original language	English
Journal	Cell Chemical Biology
Volume	25
Issue	11
Pages (from-to)	1389-1402
ISSN	2451-9456
DOIs	https://doi.org/10.1016/j.chembiol.2018.08.005
Publication status	Published - 15 Nov 2018

Keywords

Parkinson's disease
aggregation inhibitors
amyloid
biophysical analysis
high-throughput screen
membrane permeabilization
oligomerization
α-synuclein
αSO formation

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10.1016/j.chembiol.2018.08.005

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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

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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{\textquoteright} 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. Kurnik et al. developed an FRET-based high-throughput screen for inhibitors of α-synuclein aggregation, critical in development of Parkinson's disease. Out of 746,000 compounds, the 6 best hits are derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide, interact with α-synuclein's N-region and reduce oligomer-membrane interactions. We also identified compounds promoting aggregation; the 2 best share a phenyl-benzoxazol core.",

keywords = "Parkinson's disease, aggregation inhibitors, amyloid, biophysical analysis, high-throughput screen, membrane permeabilization, oligomerization, α-synuclein, αSO formation",

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}",

year = "2018",

month = nov,

day = "15",

doi = "10.1016/j.chembiol.2018.08.005",

language = "English",

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journal = "Cell Chemical Biology",

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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, vol. 25, no. 11, pp. 1389-1402. https://doi.org/10.1016/j.chembiol.2018.08.005

Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State. / Kurnik, Martin; Sahin, Cagla; Andersen, Camilla Bertel et al.
In: Cell Chemical Biology, Vol. 25, No. 11, 15.11.2018, p. 1389-1402.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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

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. Kurnik et al. developed an FRET-based high-throughput screen for inhibitors of α-synuclein aggregation, critical in development of Parkinson's disease. Out of 746,000 compounds, the 6 best hits are derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide, interact with α-synuclein's N-region and reduce oligomer-membrane interactions. We also identified compounds promoting aggregation; the 2 best share a phenyl-benzoxazol core.

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. Kurnik et al. developed an FRET-based high-throughput screen for inhibitors of α-synuclein aggregation, critical in development of Parkinson's disease. Out of 746,000 compounds, the 6 best hits are derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide, interact with α-synuclein's N-region and reduce oligomer-membrane interactions. We also identified compounds promoting aggregation; the 2 best share a phenyl-benzoxazol core.

KW - Parkinson's disease

KW - aggregation inhibitors

KW - amyloid

KW - biophysical analysis

KW - high-throughput screen

KW - membrane permeabilization

KW - oligomerization

KW - α-synuclein

KW - αSO formation

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U2 - 10.1016/j.chembiol.2018.08.005

DO - 10.1016/j.chembiol.2018.08.005

M3 - Journal article

C2 - 30197194

SN - 2451-9456

VL - 25

SP - 1389

EP - 1402

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 11

ER -

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

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Keywords

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