Use novel natural compound Sparstolonin B to treat bacterial sepsis

使用新型天然化合物Sparstolonin B治疗细菌性败血症

• 批准号: 10152442
• 负责人: Hongkuan Fan
• 金额: $ 30万
• 依托单位: ACEPRE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152442
• 关键词: Achievement; Alveolar; Animal Model; Anti-Inflammatory Agents; Antibiotics; Apoptosis; Bacteria; Bacterial Model; Binding; Cardiac Myocytes; Cardiac Myosins; Cell Culture Techniques; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chinese Herbs; Clinical Trials; Effectiveness; Epithelial Cells; Event; Evolution; Failure; Goals; HMGB1 Protein; Health Care Costs; Healthcare; Heart; HepG2; Hepatocyte; Hospitals; Hypoxia; Immune; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigational New Drug Application; Kidney; Laboratories; Ligands; Lipopolysaccharides; Lipoproteins; Lung; Microbe; Modeling; Molecular; Mouse Strains; Mus; Names; Nitric Oxide; Organ; Pathogenesis; Pathology; Patients; Pattern; Phase; Physicians; Play; Positioning Attribute; Process; Regimen; Reporting; Research Project Grants; Role; Safety; Sepsis; Septic Shock; Signal Transduction; Slice; Small Business Technology Transfer Research; Smooth Muscle Myocytes; Source; Structure; TIRAP gene; TLR2 gene; TLR4 gene; Therapeutic; Tissues; Toll-like receptors; Tubular formation; United States; United States National Institutes of Health; Vascular Endothelial Cell; cecal ligation puncture; cell type; clinical development; cost; cytokine; intraperitoneal; macrophage; male; microbial; microorganism; mortality; multiorgan injury; novel; novel therapeutics; organ injury; pathogen; pharmacokinetics and pharmacodynamics; small molecule; systemic inflammatory response

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.

摘要：根据最新的CDC报告，美国败血症的发病率超过1.7 每年百万，导致约27万人死亡，医疗费用超过200亿美元。败血症结果 从任何微生物的感染中，细菌是最常见的。病原体相关的分子 模式（PAMP），例如脂多糖（LPS）激活先天免疫细胞，尤其是巨噬细胞 以及组织常驻细胞（例如血管内皮细胞和心肌细胞）通过Toll样细胞 受体（TLR）。活化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，这些激活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，比理想的炎症反应更强 分子，作用于组织驻留细胞并导致组织损伤。此外，损坏的组织 释放内源性损伤相关的分子模式（湿），这进一步升级了炎症 通过与TLR（特别是TLR2和TLR4）结合在免疫细胞和组织驻留细胞上的结合。这 恶性循环迅速导致多器官损伤，并最终导致死亡。快速演变和复杂性 细菌败血症的病理学使治疗变得极为困难。当前管理仍然依赖 源控制，抗生素和器官支持。尽管炎症在 败血性休克的发病机理，由于各种 原因。在过去的10年中，我们和合作者1）将一种新的单一化合物与中国草药隔离开来， 确定其结构，并将其命名为Sparstolonin B（SSNB）； 2）将SSNB描述为双TLR2和TLR4 对手3）发现SSNB通过破坏Tirap和 MyD88，TLR2/4信令中的独特关键事件； 4）证明SSNB有效抑制炎症 多种细胞系和主要细胞类型对外源和内源性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 文化和活心切片； 6）报道腹膜内施用SSNB有效地降低了 LPS患者死亡； 7）在最近的初步研究中，SSNB延长了 使用盲肠连接和穿刺（CLP）模型的雄性CD-1小鼠的存活。基于这些 成就，我们处于独特的位置，可以发展为细菌败血症的新型疗法。走向这个 目标，我们建议在此IT I阶段项目中建立临床开发的可行性。我们建议 两个具体的目标：SA1。使用CLP模型确定SSNB在各种小鼠菌株中的有效性 细菌败血症；和SA2。优化SSNB的治疗方案以治疗CLP诱导的败血症。我们 相信这种安全有效的天然化合物有可能降低细菌败血症的死亡率 并大大降低医疗保健和相关成本。