东沙珊瑚共附生微生物中Keap1-Nrf2蛋白相互作用抑制剂的发现

Myocarditis is an inflammatory disease of the heart. It is reported that the number of acute myocarditis cases was approximately 1.5 million in 2013. In etiological consideration, superoxide anion, hydrogen peroxide and other reactive oxygen species (ROS) are highly produced in myocarditis and act as double-edged swords: (1) they kill pathogen and mediate the stress responsive pathways, and (2) high ROS levels decrease the capacity of the antioxidative defense system and exacerbate inflammation. Therefore, oxidative stress could be one of the pathological mechanisms of myocarditis and is considered to be one of the promising treatment targets of myocarditis. Keap1-Nrf2 signaling pathway is an important way to regulate oxidative stress,.However, covalently modification of Keap1 to activate Nrf2 has strong toxicity, even increasing the risk of cancer. Alternatively, inhibiting Keap1-Nrf2 protein-protein interaction to activate Nrf2 function is a novel strategy for myocarditis treatments. This proposal will investigate active substances of myocarditis treatments from Dongsha coral-associated microorganisms using Keap1-Nrf2 fluorescence polarization screening model. It is the first time in the world to screen Keap1-Nrf2 inhibitors from marine sources. This research demonstrates academic values in the myocarditis treatments lead discovery and may give references to the ecological development.

心肌炎是一种心脏的炎症性疾病。2013年，全球急性心肌炎病例约为150万。心肌炎中产生大量的ROS，它们在心肌炎发生发展中起到了双重作用：一杀死病原体并介导应激反应途径;二高水平ROS会降低机体抗氧化能力，加剧炎症。因此，氧化应激作为心肌炎的病理机制之一，是治疗心肌炎的有效靶点。Keap1-Nrf2信号通路是细胞内调控氧化应激反应的重要途径，但通过共价修饰Keap1而激活Nrf2的方法毒性强，甚至增加肿瘤发生。因此，通过干扰Keap1-Nrf2蛋白互作界面激活Nrf2成为治疗心肌炎活性物质发现的新策略。本研究拟以Keap1-Nrf2蛋白互作为筛选模型，从东沙珊瑚共生附微生物中发现治疗心肌炎活性物质，并对其底物蛋白作用位点及作用模式进行研究。本研究是国际上首次开展海洋来源的Keap1-Nrf2蛋白互作抑制剂的筛选，对于新型心肌炎治疗药物先导物的发现具有较高学术价值.

氧化应激作为心肌炎的病理机制之一，是治疗心肌炎的有效靶点。Keap1-Nrf2信号通路是细胞内调控氧化应激反应的重要途径，但通过共价修饰Keap1而激活Nrf2的方法毒性强，甚至增加肿瘤发生。因此，通过干扰Keap1-Nrf2蛋白互作界面激活Nrf2成为治疗心肌炎活性物质发现的新策略。本研究以东沙珊瑚及共附生微生物中的化学防御物质为切入点，对采自东沙的40余种珊瑚共附生微生物进行了纯化培养，鉴定了其中97株共生真菌和放线菌，以活性为导向，综合运用化学、现代色谱学、现代波谱学和现代分子生物学技术，对4种东沙珊瑚共附生微生物Acremonium minutisporum、Aspergillus candidus、Nigrospora chinensis及Aspergillus sp.及1种珊瑚Iciligorgia sp.化学成分进行了系统研究及生物评价，获得115个次生代谢产物，其中37个新化合物。本研究是国际上首次开展海洋来源的Keap1-Nrf2蛋白互作抑制剂的筛选，对于新型心肌炎治疗药物先导物的发现具有较高学术价值.