针对托尔类受体驱动的全身炎症,通过对药物进行先天的结构折叠进行工程
Ganna Petruk1, Manoj Puthia2, Firdaus Samsudin3
1Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden. ganna.petruk@med.lu.se.
Nature communications
|September 29, 2023
概括
一种新的基于的化合物,sHVF18,在全身感染中有效向CD14介导的炎症反应. 这种新的治疗方法在临床前模型中显示出前景,提供了一种基于自然抗感染原则的新类治疗方法.
科学领域:
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
- 生物化学 生物化学
背景情况:
- 系统性感染引发过度炎症,需要新的治疗策略.
- 氨酸衍生的C端 (TCP) 是天然的免疫调节剂,可抑制CD14介导的托尔类受体 (TLR) 依赖的免疫反应.
- 现有的治疗方法缺乏概念上的新方法来控制炎症途径.
研究的目的:
- 开发和描述一种新的基于的化合物,sHVF18,用于系统治疗与感染相关的炎症状况.
- 阐明sHVF18的结构,生化和体内特性及其作用机制.
- 在系统性感染和内毒素冲击的临床前模型中评估sHVF18的治疗疗效.
主要方法:
- 基于结构和in silico的设计,核磁共振 (NMR) 光谱学,生物物理分析和质谱学被用来描述sHVF18.8.
- 用细胞测试来研究CD14相互作用和免疫反应调节.
- 在小鼠和猪模型中进行了内毒素冲击和多微生物败血症的体内研究,以评估治疗疗效和生存率.
主要成果:
- sHVF18的设计是为了模仿自然TCP的保存天生的结构折叠,表现出形态稳定性和蛋白酶抵抗性.
- 表明该可以向CD14的脂聚糖 (LPS) 结合槽,调节免疫反应.
- 在体内研究表明,在实验性内毒素冲击中具有显著的治疗效果,并在多微生物感染模型中改善了生存率.
结论:
- sHVF18代表了一个有前途的基于的治疗候选人,用于管理系统性感染中的过度炎症.
- 该化合物有效地向CD14,利用天然抗感染原则开发药物.
- 这些发现支持开发一种基于内源性免疫调节剂的新药类,用于治疗严重感染.
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