α-Synuclein Dimers as Potent Inhibitors of Fibrillization

Kyriukha, Yevhenii; Afitska, Kseniia; Kurochka, Andrii; Sachan, Shubhra; Shvadchak, Volodymyr V.

doi:10.1016/j.bpj.2019.11.2119

Cited by 1 publication

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“…From a structural point of view, a-syn is organised in three different regions: the N-terminal domain (aa 1-60), the central NAC domain (aa 61-95) and the C-terminal domain (aa 96-140) 6 . In its monomeric soluble form, a-syn assumes an alpha helical conformation upon interaction with phospholipids, 7 while in the pathological misfolded state, it aggregates into amyloid fibrils composed by parallel hydrogen bonded b-sheets 8,9 . The formation of these aggregates causes cytotoxicity through lipid membrane permeabilisation, mitochondrial damage and oxidative stress 10 .…”

Section: Introductionmentioning

confidence: 99%

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Vittorio

Adornato

Gitto

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Parkinson’s disease is one of the most common neurodegenerative disorders in elderly age. One of the mechanisms involved in the neurodegeneration appears related to the aggregation of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To date, no highly effective treatment is currently available; therefore, there is an increasing interest in the search of new therapeutic tools. The modulation of α-syn aggregation represents an emergent and promising disease-modifying strategy for reducing or blocking the neurodegenerative process. Herein, by combining in silico and in vitro screenings we initially identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine ( 3 ) as α-syn aggregation inhibitor that was then considered a promising hit for the further design of a new series of small molecules. Therefore, we rationally designed new hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the binding mode of the newer inhibitors was predicted by docking studies.

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