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反α-Synuclein抗体的充电尾巴不会增加它们与α-Synuclein纤维的亲和力

Inga Petersen¹, Ana Godec¹, Farahnaz Ranjbarian²

¹Department of Pharmacy, Uppsala University, Uppsala, Sweden.

|August 29, 2024

概括

研究人员探索将尾添加到抗体中,通过准α-Synuclein (αSyn) 聚合物来改善帕金森病 (PD) 治疗. 负电荷的尾部意外减少了抗体与αSyn的结合,阻碍了治疗潜力.

科学领域:

神经科学是一个神经科学.
生物化学生化学
免疫学免疫学免疫学

背景情况:

阿尔法-同核素 (αSyn) 聚合是帕金森病 (PD) 和其他同核素病的标志,有助于神经元死亡.
细胞外αSyn聚合物在神经元之间传播,由与细胞表面蛋白质糖的静电相互作用促进.
目前PD的治疗策略有限,部分原因是细胞外αSyn聚合物对药物的难以获得性.

研究的目的:

为了研究与αSyn聚合物特异性抗体 (SynO2和9E4) 融合的负电荷尾是否可以增强它们的贪.
评估改性抗体在抑制细胞间传播和增强细胞外αSyn聚合物的清除中对PD治疗的潜力.

主要方法:

与酶相关的免疫吸收试验 (ELISA) 用于评估具有和没有尾的单价和双价抗体格式的激烈性.
在生理盐条件下测试了对αSyn聚合物的结合亲和力.

主要成果:

添加负电荷的尾降低了SynO2和9E4抗体对αSyn聚合物的结合强度.
这种结合的减少很可能是由于尾和负电荷的αSyn C-terminus之间的分子间排斥.
观察到尾和抗体寄生虫 (SynO2) 之间的潜在相互作用,进一步损害了结合.

结论:

测试的负电荷尾并没有像假设的那样增强抗体对αSyn聚合物的嗜好.
尾的设计需要改进,以避免对抗体结合部位 (CDR) 的干扰,并更好地模仿肝素硫酸盐相互作用.
未来的设计可能通过优化细胞外αSyn聚合物的抗体向来改善同核蛋白病变的治疗策略.

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