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 μM. 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 ion-conductance 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.

中文翻译：

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天然肉桂酸衍生物可防止α-突触核蛋白的淀粉样转化。

为了寻找能干扰α-突触核蛋白淀粉样变性的化合物，研究了9种天然和合成的肉桂酸衍生物。它们在结构上类似于姜黄素的一半，具有明显的抗聚集和抗淀粉样蛋白作用。我们已经表明，这些衍生物中的一些可以防止绵羊蛋白的淀粉样蛋白化。随后，硫黄素T结合试验表明，研究的9种化合物中有3种有效阻止了α-突触核蛋白的淀粉样蛋白转化，IC5​​0为13、50和251μM。分子建模方法揭示了三个所选配体与α-突触核蛋白原纤维的可能结合位点，而根据实验结果，单体α-突触核蛋白不与配体结合。这使我们相信化合物可能通过改变主要聚集体的结构来发挥作用，防止全长原纤维的形成。通过比浊法监测聚集，对蛋白水解裂解的敏感性，β-折叠含量的变化和扫描离子电导显微镜观察，进一步证实了配体对α-突触核蛋白聚集的抑制作用。研究的衍生物无细胞毒性，此外，在植物来源中发现了两种研究过的化合物（阿魏酸和3,4-二甲氧基肉桂酸），是人体血液中的天然代谢产物，因此它们可能是有望成为突触核蛋白疗法（包括帕金森氏病）的候选药物。和扫描离子电导显微镜。研究的衍生物无细胞毒性，此外，在植物来源中发现了两种研究过的化合物（阿魏酸和3,4-二甲氧基肉桂酸），是人体血液中的天然代谢产物，因此它们可能是有望成为突触核蛋白疗法（包括帕金森氏病）的候选药物。和扫描离子电导显微镜。研究的衍生物无细胞毒性，此外，在植物来源中发现了两种研究过的化合物（阿魏酸和3,4-二甲氧基肉桂酸），是人体血液中的天然代谢产物，因此它们可能是有望成为突触核蛋白疗法（包括帕金森氏病）的候选药物。