Rationally Designed Protein-Based Inhibitor of alpha-Synuclein Fibrillization in Cells

Priss Anastasiia; Afitska Kseniia; Galkin Maksym; Yushchenko Dmytro A.; Shvadchak Volodymyr V.

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Rationally Designed Protein-Based Inhibitor of alpha-Synuclein Fibrillization in Cells

机译：合理设计的基于蛋白质的细胞α-突触核蛋白原纤化抑制剂

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Misfolding of the neuronal protein alpha-synuclein (alpha Syn) into amyloid fibrils is involved in the development of Parkinson's disease (PD), and inhibition of this process is considered to be a promising therapeutic approach. In this work, we engineered protein inhibitors that bind to fibrils with higher affinity than the monomeric alpha Syn. They were developed based on the recent structural data of the alpha Syn fibrils and were shown to prevent fibril elongation upon binding to fibril ends. These inhibitors are highly selective to the misfolded alpha Syn, nontoxic, and active in cytosol in small concentrations. The best-performing inhibitor shows IC50 similar to 10 nM in a cell-based assay, which corresponds to the similar to 1:60 molar ratio to alpha Syn. It can suppress the formation of alpha Syn aggregates in cells that can be potentially used to slow down the spreading of the pathological aggregates from cell to cell during the course of the PD.

机译：神经元蛋白α-突触核蛋白（alpha-synuclein，α-Syn）错误折叠成淀粉样纤维参与帕金森病（Parkinson's disease，PD）的发展，抑制这一过程被认为是一种很有前途的治疗方法。在这项工作中，我们设计了蛋白质抑制剂，其与原纤维的结合亲和力高于单体α-Syn。它们是基于alpha-Syn原纤维的最新结构数据开发的，并被证明在与原纤维末端结合时可防止原纤维伸长。这些抑制剂对错误折叠的α-Syn具有高度选择性，无毒，在小浓度的细胞质中具有活性。在基于细胞的分析中，表现最好的抑制剂显示IC50类似于10 nM，与α-Syn的摩尔比类似于1:60。它可以抑制细胞内α-Syn聚集体的形成，这种聚集体可能用于减缓PD过程中病理性聚集体在细胞间的扩散。

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《Journal of Medicinal Chemistry》 |2021年第10期|共11页
作者
Priss Anastasiia; Afitska Kseniia; Galkin Maksym; Yushchenko Dmytro A.; Shvadchak Volodymyr V.;
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Acad Sci Czech Republ Inst Organ Chem &

Biochem Prague 16610 Czech Republic;

Acad Sci Czech Republ Inst Organ Chem &

Biochem Prague 16610 Czech Republic;

Acad Sci Czech Republ Inst Organ Chem &

Biochem Prague 16610 Czech Republic;

Acad Sci Czech Republ Inst Organ Chem &

Biochem Prague 16610 Czech Republic;

Acad Sci Czech Republ Inst Organ Chem &

Biochem Prague 16610 Czech Republic;

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正文语种 eng
中图分类药学;
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Rationally Designed Protein-Based Inhibitor of alpha-Synuclein Fibrillization in Cells

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