基于双试管活动的蛋白质分析揭示了EGFR导向药物的蛋白质结合的特定位置差异
Wouter van Bergen1,2, Kristina Žuna3, Jan Fiala1,2
1Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, Utrecht 3584 CH, The Netherlands.
ACS chemical biology
|July 25, 2024
概括
这项研究改进了PhosID-ABPP以比较向EGFR的药物探针,揭示了剂量依赖的结合和非向效应. PF131表现出更广泛的反应性并影响了ATP运输,而PF899针对ERBB2.
科学领域:
- 生物化学 生化学
- 化学生物学 化学生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 在氨基酸水平上了解药物标相互作用对于药物开发至关重要.
- 基于活动的蛋白质分析 (ABPP) 有助于研究药物选择性和疗效.
- 网站特定的ABPP,就像PhosID-ABPP一样,提供了关于药物参与的详细见解.
研究的目的:
- 改进PhosID-ABPP,在单个蛋白质组内进行双剂量依赖的抑制剂竞争.
- 为了比较分析两个针对表皮生长因子受体 (EGFR) 的探针,PF-06672131 (PF131) 和PF-6422899 (PF899).
- 识别探针特定的结合位点,并理解剂量依赖的蛋白质与药物相互作用.
主要方法:
- 在 timsTOF HT 质谱仪上使用了精细的 PhosID-ABPP 策略.
- 对两个针对EGFR的基于活动的探针 (ABP) 进行了比较分析:PF131和PF899.
- 研究了剂量依赖的探针与蛋白质类囊的结合以及非目标相互作用.
主要成果:
- 揭示了对氨酸的剂量依赖的探针结合偏好,即使在低纳米分子度.
- 与PF899相比,PF131表现出更广泛的目标外反应能力.
- PF899对ERBB2的标记较高,并且与其他酶中的催化囊蛋白结合;PF131通过ADP/ATP转位酶影响了ATP的运输.
结论:
- 精细的PhosID-ABPP能够对药物在目标上和目标之外的接触进行详细的,剂量和位点特定的分析.
- PF131显示出更广泛的非目标效应和ATP传输干扰,需要进一步调查.
- PF899显示了ERBB2和其他酶的特定向,为其潜在的治疗特性提供了洞察力.
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