Naturally occurring cinnamic acid derivatives prevent amyloid transformation of alpha-synuclein

In search of the compounds that interfere with amyloid transformation of alpha-synuclein, 9 natural and synthetic cinnamic acid derivatives were studied. They are structurally similar to a half of curcumin, which has pronounced anti-aggregatory and anti-amyloid effects. We have shown that some of these derivatives prevent ovine prion protein amyloidization. Subsequently, thioflavin T binding assay showed that 3 out of 9 studied compounds effectively prevented amyloid transformation of alpha-synuclein with IC50 of 13, 50 and 251 mu M. Molecular modeling approach revealed possible binding sites of the three selected ligands with alpha-synuclein fibrils, while monomeric alpha-synuclein does not bind to the ligands according to experimental results. This led us to believe that compounds may act by changing the structure of primary aggregates, preventing the formation of full-length fibrils. The inhibiting effect of the ligands on aggregation of alpha-synuclein was further confirmed by monitoring aggregation via turbidimetry, susceptibility to proteolytic cleavage, changes in beta-sheet content, and scanning ionconductance microscopy. Studied derivatives were not cytotoxic, and, moreover, two studied compounds (ferulic and 3,4-dimethoxycinnamic acid) are found in plant sources and are natural metabolites present in human blood, so they can be promising candidate drugs for synucleinopathies, including Parkinson's disease. (C) 2020 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.