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

Natural and Synthetic Derivatives of Hydroxycinnamic Acid Modulating the Pathological Transformation of Amyloidogenic Proteins

“…According to published data curcumin binds to the α-synuclein monomer, with a dissociation constant of 10 −5 M, affecting the configuration of the molecule and thus blocking oligomerization and fibrillation [ 171 ]. Using in vitro experiments on various mutant forms of α-synuclein, it has been shown that the binding of curcumin to the protein occurs in a hydrophobic non-amyloid-β component region 60–100, in which 15 aliphatic amino acids, tryptophan in position 94 or 3 alanines in position 89–91 may serve as possible binding sites [ 171 ], which also correlates with the results of molecular docking for HCA derivatives carried out using fibril structures [ 118 ].…”

“…The most active in inhibiting α-synuclein fibrillation was ferulic acid with a half-maximal inhibitory concentration of 0.8–13 µM reported in different studies [ 118 , 161 ]. It is noteworthy that some of the reported compounds such as gallic and caffeic acids were most effective in preventing seeding of aggregation by preformed fibrils, then in inhibiting aggregation when added to the monomeric α-synuclein [ 127 ].…”

“…This approach seems appropriate for the compounds that are expected to bind not to monomeric, but oligomeric forms or formed fibrils of α-synuclein, and potentially influence their assembly rate or disintegrate them. For instance, in our work [ 118 ], a few HCA and caffeic acid derivatives (ferulic acid, 3-methoxy-4-acetamidoxycinnamic acid, 3,4-DMCA) were shown to not bind to native monomeric α-synuclein, although they exerted a pronounced anti-amyloid effect. Based on docking to fibrils the hypothesis was formulated that these compounds bind to prefibrillar oligomers or small fibrils, influencing further aggregation.…”

“…A comparative analysis of the effect of 9 HCA and caffeic acid derivatives on the ability to prevent α-synuclein amyloid transformation was performed by our group: two naturally occurring (ferulic acid and 3,4-DMCA) and seven synthesized compounds [ 118 ]. Synthetic compounds were investigated in order to find out which substitutions in the structure are important for the implementation of the studied effects.…”

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…These quercetin/α-syn interactions are key to disaggregating the preformed fibrils through detaching into stable oligomers [ 200 ]. Similar to quercetin, baicalein, EGCG, gallic acids, ferulic acid derivatives, curcumin, dihydromyricetin, and salvianolic acid prevent α-syn aggregation and fibrillation in vitro and in vivo, which is associated with neuroprotection in various PD models [ 54 , 87 , 142 , 201 , 202 , 203 , 204 , 205 ].…”