通过一种新型菌机制起作用的细胞活性PAD2抑制剂的发现,特征和结构
Laura J Byrnes1, Won Young Choi1, Paul Balbo2
1Pfizer Worldwide Research and Development, Eastern Pt. Rd, Groton, Connecticut 06340-5146, United States.
ACS chemical biology
|September 24, 2024
概括
研究人员发现了一种新型的非共价性抑制剂,该抑制剂向Peptidyl Arginine Deiminase 2 (PAD2) 酶. 这种强大的PAD2抑制剂对PAD3和PAD4具有选择性,为炎症和自身免疫性疾病提供了新的治疗途径.
科学领域:
- 生物化学和药物化学 医学化学
- 酶学 是一种酶学.
- 药物发现 药物发现 药物发现
背景情况:
- 氨基氨酸减小酶 (PADs) 与炎症和自身免疫性疾病有关.
- 开发异型特异性PAD抑制剂一直是一个重大挑战.
- PAD2,PAD3和PAD4是具有不同作用的关键异构体.
研究的目的:
- 发现和表征一种强效和异型选择性抑制PAD酶的抑制剂.
- 阐明新型PAD抑制剂的抑制机制.
- 为了验证发现的抑制剂的细胞活性.
主要方法:
- 在DNA编码库中选PAD抑制剂.
- 对酶抑制和结合的生物化学和生物物理测定.
- 用于结构分析的X射线晶体学.
- 细胞测定以确认目标接触.
主要成果:
- 鉴定一种强大的非共价PAD2抑制剂,具有对PAD3和PAD4.4的选择性.
- 确定一种新的,与相竞争的抑制机制.
- 通过X射线结晶学来确认抑制剂结合的结构性.
- 在细胞环境中证明选择性PAD2抑制.
结论:
- 使用DNA编码库技术发现了一种新型的选择性PAD2抑制剂.
- 抑制剂通过一种独特的竞争机制起作用.
- 这一发现为PAD2介导疾病提供了一个有前途的化学探针和潜在的治疗.
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