Naphthoquinone-Dopamine Hybrids Inhibit α-Synuclein Aggregation, Disrupt Preformed Fibrils, and Attenuate Aggregate-Induced Toxicity.
aggregation
drug discovery
fibrous proteins
self-assembly
solid-state structures
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
ISSN: 1521-3765
Titre abrégé: Chemistry
Pays: Germany
ID NLM: 9513783
Informations de publication
Date de publication:
09 Dec 2020
09 Dec 2020
Historique:
received:
17
07
2020
pubmed:
2
9
2020
medline:
24
2
2021
entrez:
2
9
2020
Statut:
ppublish
Résumé
Accumulation and aggregation of the intrinsically disordered protein α-synuclein (α-Syn) into amyloid fibrils are hallmarks of a series of heterogeneous neurodegenerative disorders, known as synucleinopathies and most notably Parkinson's disease (PD). The crucial role of α-Syn aggregation in PD makes it an attractive target for the development of disease-modifying therapeutics that would inhibit α-Syn aggregation or disrupt its preformed fibrillar assemblies. To this end, we have designed and synthesized two naphthoquinone-dopamine-based hybrid small molecules, NQDA and Cl-NQDA, and demonstrated their ability to inhibit in vitro amyloid formation by α-Syn using ThT assay, CD, TEM, and Congo red birefringence. Moreover, these hybrid molecules efficiently disassembled preformed fibrils of α-Syn into nontoxic species, as evident from LUV leakage assay. NQDA and Cl-NQDA were found to have low cytotoxicity and they attenuated the toxicity induced by α-Syn towards SH-SY5Y neuroblastoma cells. NQDA was found to efficiently cross an in vitro human blood-brain barrier model. These naphthoquinone-dopamine based derivatives can be an attractive scaffold for therapeutic design towards PD.
Identifiants
pubmed: 32870550
doi: 10.1002/chem.202003374
doi:
Substances chimiques
Amyloid
0
Naphthoquinones
0
alpha-Synuclein
0
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
16486-16496Subventions
Organisme : Alliance Family Trust (to D.S)
Informations de copyright
© 2020 Wiley-VCH GmbH.
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