由基于结构的药物设计识别的多循环支架有效抑制了人类的P2X7受体
Adam C Oken1, Andreea L Turcu2,3, Eva Tzortzini4
1Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, USA.
Nature communications
|September 15, 2025
概括
研究人员开发了UB-MBX-46,一种强效和选择性的P2X7受体对抗剂. 这一发现通过向人类P2X7受体,为癌症和神经退行等炎症性疾病提供了治疗潜力.
科学领域:
- 结构生物学是结构生物学.
- 药理学 药理学是指药理学的学科.
- 神经科学是一个神经科学.
背景情况:
- P2X7受体 (P2X7R) 是各种疾病所涉及的炎症途径的关键调解者.
- 尽管它具有治疗潜力,但没有P2X7R抗剂得到临床批准,部分原因是对物种特异性受体差异的理解有限.
研究的目的:
- 阐明人类P2X7受体的分子特征.
- 为潜在的治疗应用设计和开发一种强效和选择性的P2X7R抗剂.
主要方法:
- 高分辨率冷电子显微镜 (cryo-EM) 用于确定人类P2X7R结构在apo和ATP结合状态.
- 人类P2X7R的冷EM结构与基于阿达曼坦的抑制剂复合在一起.
- 功能测试和分子动力学模拟以指导对手设计.
主要成果:
- 确定了人类P2X7R的高分辨率冷EM结构,与orthologs相比显示出明显的分子特征.
- 鉴定了一种基于阿达曼坦的抑制剂,并使用它来设计UB-MBX-46,这是一种具有独特多环架的新型对手.
- UB-MBX-46表现出亚纳米级强度和对人类P2X7R的高选择性,与经典的全囊结合.
结论:
- 人类P2X7R的结构和功能特征为其独特的特性提供了洞察力.
- UB-MBX-46代表了对P2X7R介导的炎症性疾病的有前途的治疗候选者.
- 这项研究强调了基于结构的药物设计在开发选择性P2X7R调节器方面的潜力.
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