Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics
Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics
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DOI：
10.1039/c7sc05323a
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发表时间：
2018-04-28
期刊：
影响因子：
8.4
通讯作者：
Zamyatina, Alla
中科院分区：
文献类型：
--
作者：
Adanitsch, Florian;Shi, Jianjin;Zamyatina, Alla
革兰氏阴性细菌脂多糖（LPS）诱导的toll样受体4 （TLR4）介导的促炎信号在免疫保护中起关键作用，可增强适应性免疫，而胞质LPS受体caspase-4/11的激活可导致细胞热亡，并与脓毒症的发生密切相关。尽管对LPS-TLR4相互作用的理解取得了巨大进展，但可预测的调节TLR4激活尚未实现。LPS诱导caspase-4/11蛋白酶活性的结构基础目前尚不清楚。通过控制TLR4信号而不触发caspase-4/11活性来调节先天和适应性免疫反应，将为安全疫苗佐剂和免疫疗法的开发开辟新的前景。我们报道发现了一种高效的糖基免疫刺激剂，对TLR4具有皮摩尔亲和力，它与caspase-4/11相互作用，促进caspase-4/11寡聚，同时消除caspase-11蛋白酶活性。模拟阴离子糖脂的合成LPS的α， α -(11 1')键双糖核的刚性和扭曲分子形状解释了tlr4介导的NF-kappa B信号和调节caspase-4/11激活的物种无关和可调节的。通过基于晶体结构的设计和先进的合成化学，我们创建了一套多功能探针，用于研究caspase-4/11活化的结构基础，并建立了一种与诱导caspase-11蛋白酶活性分离的可控TLR4介导的细胞因子释放的化学策略。
Gram-negative bacterial lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) mediated pro-inflammatory signaling plays a key role in immunoprotection against infectious challenges and boosts adaptive immunity, whereas the activation of the cytosolic LPS receptor caspase-4/11 leads to cell death by pyroptosis and is deeply implicated in the development of sepsis. Despite tremendous advances in the understanding of the LPS-TLR4 interaction, predictably regulated TLR4 activation has not yet been achieved. The structural basis for the induction of caspase-4/11 protease activity by LPS is currently unknown. The modulation of innate and adaptive immune responses through the controlled induction of TLR4 signaling without triggering caspase-4/11 activity would open novel perspectives in the development of safe vaccine adjuvants and immunotherapeutics. We report the discovery of highly potent glycan-based immunostimulants with picomolar affinity for TLR4 which interact with caspase-4/11 and promote caspase-4/11 oligomerization while abolishing caspase-11 protease activity. The rigidity and twisted molecular shape of the alpha,alpha-(1 1')-linked disaccharide core of synthetic LPS mimicking anionic glycolipids accounted for both species-independent and adjustable TLR4-mediated NF-kappa B signaling and the modulation of caspase-4/11 activation. By the use of crystal structure based design and advanced synthetic chemistry we created a set of versatile probes for studying the structural basis of caspase-4/11 activation and established a chemical strategy for controllable TLR4 mediated cytokine release which is dissociable from the induction of caspase-11 protease activity.