脓毒血症是一种由感染、内毒素引起的全身性炎症反应综合征。内毒素LPS通过LBP-CD14-TLR4/MD2的传递激活急性炎症反应。虽然CD14基因敲除可以降低机体对LPS敏感性，但相对TLR4/MD2复合物，CD14抑制剂抗炎药物研究鲜有报道。我们长期从事TLR4通路的抗炎药物化学和药理研究，前期工作通过对LBP与CD14瞬态蛋白相互作用分析，设计得到的多肽类抑制剂，可直接结合CD14并显著抑制LPS诱导的炎症因子释放。我们假设：以此类多肽抑制剂GI-16、YK-12和LN-22为先导，了解其与CD14的结合机制，有望设计和发现新的治疗脓毒血症的候选新药，增强对CD14靶点的认识。本项目拟通过系列分子层面研究，深入阐明此类抑制剂与CD14的结合机制；以其为先导基于分子对接、共晶结构，设计合成一系列衍生肽并进行抗炎测试和体内外药理研究。项目将为脓毒血症治疗提供新的靶点和药物结构先导。

Sepsis is a SIRS (Systemic Inflammatory Response Syndrome) that induced by infection and endotoxin. Endotoxin (LPS) activates acute inflammatory response through the LBP-CD14-TLR4/MD2 signal pathway. Compared with TLR4/MD2 complex, the anti-inflammatory drugs based on CD14 inhibitors are barely investigated, although the body sensitivity against LPS could be reduced by CD14 gene knockout. Our group has been carrying out the medicinal chemistry and pharmacological research of anti-inflammatory drugs on TLR4 signal pathway for a long term. In the preliminary study, CD14 inhibitory peptides were designed through the analysis of LBP and CD14 transient PPI (Protein-Protein Interaction) and it turned out that the peptides could directly bind to CD14 and inhibit the LPS induced inflammatory cytokine release. Thus, we assumed that taking these inhibitory peptides (YK-12, GI-16, and LN-22) as lead compounds and understanding the CD14 binding mechanism could help us to design and discover new drug candidates for sepsis therapy and to enhance our understanding of the therapeutic target CD14. In this project, we plan to further clarify the binding mechanism between this kind of inhibitor and CD14 through a series of molecule-level research, to design and synthesize a series of derivative peptides through molecular docking and co-crystallization analysis, and to test their anti-inflammatory activities and have pharmacological research. We hope the project will provide a new drug target and new drug leading structures for sepsis therapy.