筛选鉴定非经典炎症小体-GSDMD小分子抑制剂作为预防及治疗脓毒症的新策略

脓毒症(Sepsis)是由病原体感染引起的宿主抗感染免疫失调所导致的全身炎症反应与多器官衰竭综合征，其病情进展迅速且病死率高。目前临床中尚无针对脓毒症的药物及治疗方案。因此，寻求切实有效的脓毒症治疗措施是亟待解决的科学问题。近期研究发现非经典炎症小体及其下游的成孔分子gasdermin D（GSDMD）在脓毒症发生发展过程中发挥关键作用。GSDMD缺失能够逆转由LPS诱发的小鼠脓毒症死亡。基于此，阻断非经典炎症小体通路尤其是GSDMD将会是治疗脓毒症切实可行的策略。在本课题研究中，申请者将筛选与鉴定非经典炎症小体与GSDMD的小分子抑制剂，并从细胞和动物疾病模型两方面验证筛选到的抑制剂效果，同时利用冷冻电镜、蛋白质晶体解析及结构模型构建在结构层面解析该抑制剂发挥作用的分子基础，以期为预防和治疗脓毒症提供新的临床治疗策略方案指导。

Sepsis is a potentially life-threatening condition caused by the body's response to an infection, which triggers changes that can damage multiple organ systems. According to the Mayo Clinic, septic shock has close to a 50 percent mortality rate. Currently, antibiotics and supportive care are the only treatment strategies to sepsis available in clinic, which lacks specificity and efficiency. Therefore, there is an urgent need to develop novel and efficient targeted therapies for sepsis. Progress of recent research identified non-canonical inflammasome and its downstream pore-forming molecule, gasdermin D (GSDMD), as the Achilles’ Heel of sepsis, placing them as the key to understand and treat sepsis. The overall goal of this proposal is to screen for non-canonical inflammasome and GSDMD inhibitors and evaluate their contribution in preventing and treating sepsis. We will perform high throughput screens to identify candidates of small molecule inhibitors against GSDMD, and assess the effect of these hits on pyroptosis and sepsis in cell-based platform as well as mouse models of sepsis. Moreover, cryo-EM, crystallography and structural modeling will be conducted to obtain structural information of GSDMD and the GSDMD-NT pore, which will guide the identification and optimization of inhibitors that block pore formation and pyroptosis. These studies will deepen our understanding of host-microbial interactions and provide novel therapeutic strategies for the treatment of infectious diseases including sepsis.