The Key Features of Catechols and α,β Unsaturated Carbonyl Moieties: Interaction With α-syn Hydrophobic peptide and Activation of Catecholamines Pathway in Cells

Graphical Abstract

Naturally-occurring compounds inhibit α-synuclein and the peptide ⁷¹VTGVTAVAQKTV⁸² and activate of the catecholamines pathway.

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, and the treatment focuses on delivering L-DOPA. In this work, we isolated and tested several compounds against α-synuclein and the hydrophobic peptide ⁷¹VTGVTAVAQKTV⁸² including flavonols (kaempferol, quercetin, and isorhamnetin), isoflavone (genistein) and flavone (luteolin), and compounds with α, β unsaturated carbonyl moieties such as chlorogenic acid and the depsidone fumarprotocetraric acid. Most compounds inhibit both α-synuclein and hydrophobic peptide fibrillization. Moreover, ITC experiments showed a Kd varying from 9 to 20 μM, and ΔH values vary from −1.94 to −10.5 among the compounds. Docking experiments showed the intermolecular interactions within the sites 2, 9, and 3/13 of α-synuclein, and with the hydrophobic peptide. In cultured cells, the presence of the compounds showed that most of them can promote cell proliferation and differentiation. Considering that treatments for neurodegenerative disorders, including PD, is only palliative the evaluation of these compounds that can prevent the fibrillization of α-synuclein and stimulate the catecholamines pathway is promising.