Naphthoquinone–Dopamine Hybrids Inhibit α-Synuclein Aggregation, Disrupt Preformed Fibrils, and Attenuate Aggregate-Induced Toxicity

Ashim Paul, Adi Huber, Daniel Rand, Fabien Gosselet, Itzik Cooper, Ehud Gazit, Daniel Segal

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish
Pages (from-to)16486-16496
Number of pages11
JournalChemistry - A European Journal
Issue number69
StatePublished - 9 Dec 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Wiley-VCH GmbH


This research was supported in part by the Alliance Family Trust (to D.S). Authors thank members of the E.G. and D.S. research groups for helpful discussions.

FundersFunder number
Alliance Family Trust


    • aggregation
    • drug discovery
    • fibrous proteins
    • self-assembly
    • solid-state structures


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