通过集成计算抗体设计工作流程,克服了 Galectin-3BP 的结构复杂性
Andrielly H S Costa1, Eduardo M Gaieta1, Aline O Albuquerque2
1Postgraduate Program in Computational and Systems Biology, Oswaldo Cruz Foundation (Fiocruz), 21040-900, Rio de Janeiro, Brazil; Structural and Functional Biology in Biopharmaceuticals Group - Fiocruz Ceará, 61760-000, Eusébio, Brazil.
研究人员开发了一种计算方法来设计针对加列-3结合蛋白 (Gal-3BP) 的抗体,克服了诸如糖化等挑战. 优化抗体候选人被确定用于治疗癌症的治疗开发.
科学领域:
- 计算生物学和生物信息学
- 结构生物学 结构生物学
- 免疫学和抗体工程 免疫学和抗体工程
背景情况:
- 素-3结合蛋白 (Gal-3BP) 是一种重要的瘤学点,但其复杂的结构,包括糖化和异质性,阻碍了治疗性抗体的发展.
- 现有的抗体开发是昂贵和实验密集的,需要新的方法来准像Gal-3BP.BP这样的复杂糖蛋白.
研究的目的:
- 建立一个整合性的in-silico工作流程,用于设计针对加勒-3结合蛋白 (Gal-3BP) 的治疗抗体.
- 识别和设计可以访问Gal-3BP上的糖屏蔽表位体的抗体候选者,用于潜在的癌症治疗.
主要方法:
- 利用结构预测,分子动力学 (MD) 模拟和抗体工程来分析Gal-3BP结构,寡合化和N-甘氨酸多样性.
- 采用3D Zernike描述器用于脚手架选择和库采矿用于抗体模板识别.
- 应用代工程,包括点突变和CDR交换,然后加热MD和高斯加速MD (GaMD) 进行稳定性和结构分析.
主要成果:
- 在Gal-3BP BACK域中确定了两种无甘氨酸表位 (E1和E2).
- 选择并设计了兼容的抗体支架 (BDBV-43为E1,E2-Ab1为E2),具有改进的相互作用概况和稳定性.
- GaMD模拟揭示了重新组织的构造景观和工程抗体中适度的自由能量配置变化.
结论:
- 加勒-3结合蛋白 (Gal-3BP) 是一个可处理的治疗点,已确定了优化的抗体候选者.
- 综合计算管道显示了设计抗体对Gal-3BP等结构复杂蛋白质的显著潜力.
- 开发出来的抗体可以接触到受糖屏蔽影响最小的表位,为新型癌症疗法铺平了道路.
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