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解读具有不同架构的生物结合物中的聚合物相互作用,通过通过时间解析的有限蛋白解质质谱法进行结构分析

Prisca Hamm¹, Marc D Driessen^2,3, Niklas Hauptstein¹

¹Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany.

Angewandte Chemie (International ed. in English)

|January 9, 2025

概括

有限蛋白质溶解质谱学 (LiP-MS) 揭示了像聚乙烯糖醇 (PEG) 这样的聚合物如何与干扰素-α2a (IFN) 相互作用. 这种技术增强了对生物结合物开发的过渡性蛋白质聚合物相互作用的理解.

科学领域:

生物化学生物化学
蛋白质组学是指蛋白质组学.
聚合物化学聚合物化学

背景情况:

治疗性蛋白质经常被聚合物修改,以改善它们的药理动力学特性.
了解聚合物和蛋白质之间的特定相互作用对于设计有效的生物结合物至关重要.
目前的方法往往缺乏对这些聚合物-蛋白相互作用的详细描述.

研究的目的:

通过有限蛋白解质质谱法 (LiP-MS) 研究和结构性描述干扰素-α2a (IFN) 与各种聚合物之间的相互作用.
为了比较聚乙烯糖醇 (PEG),线性聚糖醇 (LPG) 和聚二氧化 (POX) 与IFN-α2a的相互作用概况.
阐明不同聚合物链接剂 (BCN和DBCO) 对蛋白质-聚合物相互作用的影响.

主要方法:

用有限蛋白质解质质谱法 (LiP-MS) 来定量IFN-α2a上的素裂变动态.
10kDa聚合物 (PEG,LPG,POX) 的特定部位生物结合,以使用循环子素连接剂 (BCN/DBCO) 进行亚酸功能化IFN-α2a.
进行了全原子分子动力学模拟,以分析短暂的蛋白质聚合物相互作用.

主要成果:

LiP-MS揭示了不同的相互作用概况:PEG和LPG与IFN-α2a表现出类似的相互作用,而POX表现出减少的表面相互作用.
分子动力学模拟证实了PEG,LPG和POX与IFN的短暂 (<50 ns) 和明显的相互作用概况.
通过 BCN 链接器形成的 IFN 聚合物合物表现出同质的裂变动态,这表明与 DBCO 链接合物相比,IFN 结构更为保守.

结论:

时间解析的LiP-MS是一种强大的工具,用于量化裂变事件,并增强对过渡性蛋白质-聚合物相互作用的结构理解.
聚合物和链接剂的选择显著影响生物结合物的相互作用概况和结构动态.
这些发现为合理设计具有调制药理动学的新型蛋白质聚合物生物结合物提供了宝贵的见解.

关键词:

15N 标签 15N 的标签干扰素α2a是一种干扰素.有限的蛋白质分解生物结合物是一种生物结合物.定量化的蛋白质组学.

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