Use novel natural compound Sparstolonin B to treat bacterial sepsis

摘要：根据CDC最新报告，美国脓毒症发病率超过1.7 每年造成约 27 万人死亡和超过 200 亿美元的医疗费用。败血症结果 任何微生物的感染，其中最常见的是细菌。病原体相关分子 模式（PAMP），例如脂多糖（LPS）激活先天免疫细胞，特别是巨噬细胞， 以及组织驻留细胞，例如血管内皮细胞和心肌细胞，通过Toll-like 受体（TLR）。激活的巨噬细胞吞噬并杀死微生物。一方面，这个过程可能 减少微生物负荷并限制感染。另一方面，这些活化的巨噬细胞可能会引起 通过分泌过量的细胞因子和氧化作用，产生比预期更强的炎症反应 分子，作用于组织驻留细胞并导致组织损伤。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 TLR（特别是 TLR2 和 TLR4）结合而级联。这个 恶性循环迅速导致多器官损伤，最终导致死亡。快速演变和复杂性 细菌性败血症的病理学特征使其极其难以治疗。目前的管理层仍然依赖 源头控制、抗生素和器官支持。尽管炎症在疾病中起着关键的有害作用 败血性休克的发病机制，由于各种原因，尚未证明抗炎方法是成功的 原因。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，并将其命名为Sparstolonin B (SsnB)； 2) 将 SsnB 表征为双重 TLR2 和 TLR4 对手; 3）发现SsnB通过破坏TIRAP和TLR2/4之间的相互作用来拮抗TLR2/4 MyD88，TLR2/4信号传导中独特的关键事件； 4）证明SsnB能有效抑制炎症 多种细胞系和原代细胞类型对外源和内源 TLR2/4 配体的反应； 5） 表明SsnB抑制缺氧诱导的心肌细胞炎症反应和细胞凋亡 文化和活体心脏切片； 6)报道腹腔注射SsnB可有效降低 LPS内毒素血症小鼠死亡； 7) 在最近的初步研究中表明，SsnB 延长了 使用盲肠结扎穿刺 (CLP) 模型观察雄性 CD-1 小鼠的存活情况。在这些基础上 取得的成就表明，我们在开发 SsnB 作为细菌性脓毒症的新型疗法方面处于独特的地位。朝这个方向 目标，我们建议在此 STTR 一期项目中建立临床开发的可行性。我们建议 两个具体目标：SA1。使用 CLP 模型确定 SsnB 在各种小鼠品系中的有效性 细菌性败血症；和SA2。优化 SsnB 治疗 CLP 引起的脓毒症的治疗方案。我们 相信这种安全有效的天然化合物有可能降低细菌性败血症的死亡率 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.