Inhibition of Prion Propagation by 3,4‐Dimethoxycinnamic Acid

Abstract

Neurodegenerative diseases are associated with accumulation of amyloid-type protein misfolding products. Prion protein (PrP) is known for its ability to aggregate into soluble oligomers that in turn associate into amyloid fibrils. Preventing the formation of these infective and neurotoxic entities represents a viable strategy to control prion diseases. Numerous attempts to find dietary compounds with anti-prion properties have been made; however, the most promising agent found so far was curcumin, which is poorly soluble and merely bioavailable. In the present work, we identify 3,4-dimethoxycinnamic acid (DMCA) which is a bioavailable coffee component as a perspective anti-prion compound. 3,4-Dimethoxycinnamic acid was found to bind potently to prion protein with a Kd of 405 nM. An in vitro study of DMCA effect on PrP oligomerization and fibrillization was undertaken using isothermal titration calorimetry (ITC), dynamic light scattering (DLS) and circular dichroism (CD) methodologies. We demonstrated that DMCA affects PrP oligomer formation reducing the oligomer content by 30-40%, and enhancing SH-SY5Y cell viability treated with prion oligomers. Molecular docking studies allowed to suggest a site where DMCA is able to bind stabilizing PrP tertiary structure. We suggest that DMCA is a perspective dietary compound for prophylaxis of neurodegenerative diseases that needs further research. Copyright © 2017 John Wiley & Sons, Ltd.

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

“…The majority of anti-prion compounds, including polyphenols, bind precisely to this partially hydrophobic cavity surrounded by polar and charged residues. For example, according to docking and in some cases experimental confirmation, it is the binding site of curcumin and other HCA derivatives [ 119 , 120 ], chalcone derivatives [ 121 , 122 ], and other polyphenolic compounds. This was additionally confirmed by the effectiveness of the anti-prion activity of the compounds selected in this work by virtual screening.…”

“…First of all, 3,4-DMCA was docked; 3,4-DMCA also has much better solubility in water—the apparent solubility of 3,4-DMCA is 5 mM against that of 0.5 mM for curcumin. Although the binding of 3,4-DMCA to the site found for curcumin cannot be excluded, a more energy-efficient site between H2 and H3 helices was found when modeling the binding of 3,4-DMCA to PrP, and the suggested binding mode is supported by hydrogen bonds and electrostatic interactions with R139 and N162 residues [ 119 ] with dG values of −4.5 kcal/mol against −3 kcal/mol for curcumin ( Figure 4 ).…”

“…Experimental studies confirmed the results of molecular modeling of the interaction of 3,4-DMCA with a prion monomer. Using various approaches, the effects of 3,4-DMCA, ferulic acid, and 7 chemical derivatives bearing different substituents in o -, m -, and p - positions of cinnamic acid were studied for anti-prion activity [ 119 , 144 ]. Among naturally occurring HCAs, the most promising effect was shown for 3,4-DMCA.…”

“…In particular, it was shown that they suppress the pathological transformation of PrP under the closest to natural conditions—when preformed amyloid fibrils are added to PrP monomers, i.e., during so-called seeding. The studied derivatives were also able to increase the viability of SH-SY5Y neuroblastoma cells after the addition of prion oligomers, which indicates a decrease in prion neurotoxicity under the influence of some HCA derivatives [ 119 , 144 ].…”

“…In one experiment, polyphenol-rich foods were excluded from the volunteers’ diets, but a mixture of seven spices was added: turmeric, coriander seeds, caraway seeds, dried Indian gooseberries, cayenne pepper, cinnamon and cloves in a ratio of 8:4:4:4:2:1:1 with a total mass of 12 g. The concentration of cinnamic acid in blood plasma then reached 342 ± 83 nM 0.5–4 h after ingestion [ 185 ]. However, HCA derivatives, which prevent the pathological transformation of PrP [ 119 ] (see also Section 5 ) and α-synuclein [ 118 ], may be equally important coffee components. According to our preliminary data, synthetic 3-methoxy-4-acetamidoxycinnamic acid, which has pronounced anti-amyloid activity against α-synuclein, is present in coffee extracts.…”