Use novel natural compound Sparstolonin B to treat bacterial sepsis

摘要：根据疾控中心的最新报告，美国脓毒症的发病率超过1.7 每年造成约27万人死亡，医疗费用超过200亿美元。脓毒症结果 不受任何微生物的感染，细菌是最常见的。病原体相关分子 模式(PAMP)，如脂多糖(LPS)，激活天然免疫细胞，特别是巨噬细胞， 以及血管内皮细胞和心肌细胞等组织驻留细胞通过Toll样蛋白 受体(TLR)。被激活的巨噬细胞吞噬并杀死微生物。一方面，这一过程可能 减少微生物负荷，限制感染。另一方面，这些激活的巨噬细胞可能会引发 分泌过量的细胞因子和氧化反应，比理想的炎症反应更强 分子，作用于组织驻留细胞，导致组织损伤。此外，受损的组织 释放内源性损伤相关分子模式(DAMP)，进一步加剧炎症 通过与免疫细胞和组织驻留细胞上的TLRs，特别是TLR2和TLR4结合而级联。这 恶性循环迅速导致多器官损伤，最终导致死亡。快速进化和复杂性 细菌性败血症的病理特点使其极难治疗。目前的管理层仍然依赖于 源头控制、抗生素和器官支持。尽管炎症在糖尿病的发病中起着关键的有害作用 感染性休克的发病机制，目前还没有抗炎方法被证明是成功的，因为 理由。在过去的10年里，我们和合作者1)从中草药中分离出一种新的单一化合物， 确定了其结构，定名为玄参甲素B(SSnB)；2)将其鉴定为TLR2和TLR4双重结构 3)发现SSNB通过破坏TIRAP与TIRAP之间的相互作用而拮抗TLR2/4 MyD88，TLR2/4信号转导中的一个独特的关键事件；4)证实了SSNB有效地抑制炎症 多种细胞系和原代细胞对外源性和内源性TLR2/4配体的反应；5) 表明SSNB抑制低氧诱导的心肌细胞炎症反应和细胞凋亡 培养和活体心脏切片中；6)报道称，在腹膜腔内注射SSNB有效地降低了 内毒素血症小鼠死亡；7)最新的初步研究表明，SSNB延长了 使用盲肠结扎和穿孔(CLP)模型的雄性CD-1小鼠的存活。在此基础上 由于取得的成就，我们处于独特的地位，可以开发SSNB作为一种治疗细菌性脓毒症的新疗法。朝向这个方向 为了实现这一目标，我们在这个STTRI期项目中提出了建立临床开发可行性的建议。我们建议 两个具体目标：SA1。利用CLP模型建立SSNB对不同品系小鼠的疗效 细菌性败血症；和SA2。目的：优化SSNB治疗CLP脓毒症的治疗方案。我们 相信这种安全有效的天然化合物有可能降低细菌性脓毒症的死亡率 并极大地降低医疗保健和相关成本。

Summary: According to the most recent CDC report, the incidence of sepsis in the United States is over 1.7 million each year, resulting in about 270,000 deaths and over $20 billion in healthcare costs. Sepsis results from infection of any microorganisms with bacteria being the most common. Pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides (LPS) activate innate immune cells, macrophages in particular, as well as tissue resident cells such as vascular endothelial cells and cardiomyocytes through Toll-like receptors (TLRs). The activated macrophages engulf and kill the microbes. On the one hand, this process may reduce microbial load and limit the infection. On the other hand, these activated macrophages may elicit a stronger than desirable inflammatory response by secreting excess amounts of cytokines and oxidative molecules, acting on tissue resident cells and leading to tissue damage. Moreover, the damaged tissues release endogenous damage-associated molecular patterns (DAMPs), which further escalate the inflammatory cascade through binding to TLRs, particularly TLR2 and TLR4, on immune cells and tissue resident cells. This vicious cycle rapidly leads to multi-organ injury, and eventually death. The quick evolution and the complexity of the pathology of bacterial sepsis make it extremely difficult to treat. Current management still relies on source control, antibiotics, and organ support. Although inflammation plays a key detrimental role in the pathogenesis of septic shock, no anti-inflammatory approaches have been proved successful due to various reasons. In the past 10 years, we and collaborators 1) isolated a new single compound from Chinese herbs, determined its structure, and named it Sparstolonin B (SsnB); 2) characterized SsnB as a dual TLR2 and TLR4 antagonist; 3) discovered that SsnB antagonizes TLR2/4 by disrupting the interaction between TIRAP and MyD88, a unique key event in TLR2/4 signaling; 4) demonstrated that SsnB effectively inhibits inflammatory responses of multiple cell lines and primary cell types to both exogenous and endogenous TLR2/4 ligands; 5) showed that SsnB inhibits the hypoxia-induced cardiomyocyte inflammatory response and apoptosis in cell culture and in live heart slices; 6) reported that intraperitoneal administration of SsnB effectively reduced the death of LPS endotoxemic mice; and 7) in most recent preliminary study demonstrated that SsnB prolonged survival of male CD-1 mice using a cecal ligation and puncture (CLP) model. On the basis on these achievements, we are in a unique position to develop SsnB as a novel therapy for bacterial sepsis. Toward this goal, we propose in this STTR phase I project to establish the feasibility of clinical development. We propose two specific aims: SA1. To establish the effectiveness of SsnB in various mouse strains using the CLP model of bacterial sepsis; and SA2. To optimize the therapeutic regimen of SsnB to treat CLP-induced sepsis. We believe this safe and effective natural compound has the potential to reduce the mortality of bacterial sepsis and reduce healthcare and related costs tremendously.