Chemical approach for the structure and function of key compounds in innate immunity

细菌细胞壁成分被认为是动物的有效免疫刺激剂。在本研究中，我们研究了基于细菌细胞壁组分的化学结构来理解免疫刺激的识别机制，例如肽聚糖的胞壁酰二肽（MDP）和脂多糖的糖脂部分脂质A，我们已经揭示了它们是免疫刺激的最小活性组分。自从发现MDP作为活性组分以来，MDP受体已经被许多研究者研究，我们发现，由密歇根大学的Inohara在动物细胞中发现的NOD 2，是MDR的受体，我们用合成化合物证明，NOD 2也识别具有四糖或八糖的MDP的更大结构，并且它导致激活免疫系统。我们还发现NODI存在于动物细胞的细胞质中，是革兰氏阴性菌肽聚糖的一种成分，即二氨基庚二酸肽的受体。另一方面，动物免疫细胞膜上的受体TLR 2识别疏水基团修饰的肽聚糖部分结构，脂多糖及其活性部分类脂A被认为是TLR 4的配体。为了了解激活机制，我们与东京大学的Miyake合作研究了与TLR 4偶联的蛋白质MD 2的作用，发现TLR 4-MD 2复合物是脂多糖和脂质A的真实的功能性受体。我们还合成了一系列具有拮抗或内毒素活性的类脂A类似物，并尝试通过分子模拟计算和生物活性观察来分析其内毒素和拮抗活性的结构特征。

Bacterial cell wall components have been known as potent immunostimulator for animals. In this research, we investigated to understand the recognition mechanism of the immunostimulation based on the chemical structure of the bacterial cell wall components such as muramyldipeptide (MDP) of peptidoglycan, and lipid A, a glycolipid part of lipopolisaccharide, which we had revealed as the minimal active components for the immunostimulation.Since the discovery of MDP as the active component, the receptor of MDP have been investigated by many researchers, and we found that N0D2, which was found in animal cells by Inohara at University of Michigan, is the receptor for MDR We demonstrated with synthetic compounds that N0D2 also recognizes the bigger structure having MDP with tetrasaccharide or octasaccharide and it leads to activate the immune system. We also found NODI, which is in cytoplasm of animal cells, is the receptor of peptides containing diaminopimeric acid, a component of gram-negative bacterial peptidoglycan. On the other hand, it was shown that TLR2, a receptor on membrane of animal immune cells, recognizes the peptidoglycan partial structures modified with hydrophobic group.Lipopolysaccharide and its active moiety lipid A had known as the ligand of TLR4. In order to understand the activation mechanism, we investigated the role of MD2, which is a protein coupled with TLR4, as the collaboration with Miyake at the University of Tokyo, and found TLR4-MD2 complex is a real functional receptor of lipopolysaccharide and lipid A. We also synthesized a series of lipid A analogues that show antagonistic or endotoxic activity, and tried to analyze the structural characteristic of the endotoxic and antagonistic activity with the molecular modeling calculation and observation of the bioactivity.