一种SLC15A4的构造锁定抑制剂,具有TASL蛋白静止抗炎活性
Andras Boeszoermenyi1, Léa Bernaleau2, Xudong Chen3
1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Nature communications
|October 20, 2023
概括
研究人员发现了feeblin,一种新型化合物,通过向SLC15A4-TASL模块来抑制托尔类受体7/8 (TLR7/8) 途径. 这一发现为诸如系统性红斑狼之类的自身免疫性疾病提供了新的治疗策略.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 失调的先天免疫系统病原体识别途径与自身免疫性疾病有关.
- 开发针对这些复杂分子网络的向疗法仍然是一个挑战.
研究的目的:
- 为了确定核酸感应TLR7/8通路的新型抑制剂.
- 通过针对SLC15A4-TASL适配器模块来研究自身免疫疾病的新治疗策略.
主要方法:
- 利用表型分析来监测免疫适配器TASL降解.
- 鉴定出Feeblin是TLR7/8通路的抑制剂.
- 通过高分辨率冷电子显微镜 (cryo-EM) 用SLC15A4.4确定了feeblin的结构.
主要成果:
- 费布林通过破坏SLC15A4-TASL适配器模块来抑制TLR7/8通路,导致TASL退化.
- 冷-EM结构揭示了Feeblin与SLC15A4结合,防止TASL相互作用.
- 费布林在阻断系统性红斑狼患者人体免疫细胞反应方面表现出有效性.
结论:
- 费布林代表了开发针对TLR7/8-IRF5信号通路的治疗方法的概念验证.
- 该机制涉及TASL的形态转换和蛋白静态调节.
- 这种方法对治疗全身性红斑狼和潜在的其他自身免疫性疾病充满希望.
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