选择性激活PFKL可以抑制细胞氧化突发
Neri Amara1, Madison P Cooper2, Maria A Voronkova2
1Physiological Chemistry Department, Genentech, South San Francisco, CA 94080, USA.
Cell
|July 28, 2021
概括
新的化合物NA-11和LDC7559通过激活果酶-1 (PFKL) 来抑制中性粒细胞的NADPH氧化酶 (NOX2). 这减少了炎症和组织损伤, 为ARDS等疾病提供了潜在的治疗策略.
科学领域:
- 生物化学
- 免疫学
- 药理学
背景情况:
- 中性粒细胞利用NADPH氧化酶 (NOX2) 杀死病原体,但其过度活化会导致ARDS等炎症性疾病.
- 酸途径产生NADPH,推动NOX2活动.
研究的目的:
- 确定抑制中性粒细胞中NOX2依赖氧化突发的小分子.
- 研究新型抑制剂的作用机制.
主要方法:
- 采用无偏的化学蛋白质策略来选抑制剂.
- 使用结构生物学来阐明药物向相互作用.
- 评估了依赖NOX2的中性粒细胞功能,包括NETosis和组织损伤.
主要成果:
- 确定了LDC7559和一个更强大的类似物,NA-11,作为中性粒细胞氧化突发的抑制剂.
- 证实NA-11激活肝脏类型的果酶-1 (PFKL),抑制酸通路的流量.
- 在接受NA-11治疗的中性粒细胞中观察到中性粒细胞死亡 (NETosis) 和组织损伤的减少.
- 确定NA-11选择性地与PFKL结合,不影响PFKP和PFKM.
结论:
- 在免疫细胞中,NA-11可选择性地激活PFKL,这是主要的果酶-1异型.
- 这种激活提供了一种抑制NOX2活性和减轻中性粒细胞驱动的炎症的新机制.
- 作为一种有价值的研究工具和潜在的炎症治疗剂.
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