在原生蛋白质上进行化学和区域选择性素修饰
Maria J Matos1, Bruno L Oliveira1, Nuria Martínez-Sáez1
1Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge , U.K.
Journal of the American Chemical Society
|February 24, 2018
概括
计算机设计的试剂可以精确地修改原生蛋白质上的单 lysine 残留物. 这有助于在没有基因工程的情况下进行治疗和生物研究的蛋白质结合.
科学领域:
- 生物结合化学
- 蛋白质工程
- 化学生物学
背景情况:
- 蛋白质修饰对于扩大治疗和功能应用至关重要.
- 现有的方法通常需要基因修改或仅限于蛋白质末端.
- 选择性结合在蛋白质化学中仍然是一个挑战.
研究的目的:
- 使用计算机设计的试剂开发一种选择性蛋白质修饰的新方法.
- 在没有工程技术的情况下实现对原生蛋白序列的单个氨酸残留物的修饰.
- 证明这种方法在制造功能蛋白合物方面具有实用性.
主要方法:
- 硫烯酸试剂的计算机辅助设计.
- 使用氨酸残留物的固有反应性差异进行区域选择性.
- 在生物相容条件下进行反应 (37 °C,pH 8.0).
主要成果:
- 在五种不同的蛋白质上成功修改了单个氨酸残留物,包括治疗性抗体Trastuzumab.
- 基于 lysine pKa 和本地微环境,通过计算预测的地点选择性.
- 证明了对氨酸的化学选择性,而不是对氨酸等其他核爱素的选择性.
- 用于细胞成像和诊断的功能蛋白结合物.
结论:
- 开发的方法提供了一个简单,强大的非遗传方法,用于选择性蛋白质修饰.
- 这项技术可以为各种生物和治疗应用创造明确的蛋白质合物.
- 区域选择性氨酸修饰为高级应用提供了进一步的生物结合.
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