SsnB, a Chinese herb-derived selective TLR antagonist

SsnB，一种中药来源的选择性 TLR 拮抗剂

基本信息

批准号：
8301844
负责人：
Daping Fan
金额：
$ 20.55万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301844
关键词：
Acute Adaptor Signaling Protein Alternative Therapies Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Attenuated Autoimmune Process Bacteria Binding Blood Books Cell membrane Cells China Chinese Herbs Chinese Traditional Medicine Chronic Clinic Clinical Colitis Complementary and alternative medicine Dendritic Cells Development Diabetes Mellitus Disease Dose Drug Design Endotoxemia Escherichia coli Future Herb Homologous Gene Immune In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 Invaded Investigation Language Lead Lentivirus Vector Leucine-Rich Repeat Ligands Mammalian Cell Measures Mediating Membrane Methods Modality Modern Medicine Molecular Monitor Mus Natural Immunity Organ Organism Pain Pathogenesis Pharmacology Plants Plasma Production Proteins Publishing Qi Receptor Signaling Research Sepsis Signal Pathway Signal Transduction Site Structure Survival Rate System Systemic Lupus Erythematosus TLR1 gene TLR2 gene TLR3 gene TLR4 gene Tertiary Protein Structure Testing Therapeutic Therapeutic Effect Tissues Toll-like receptors Toxic effect Translating Virus Work base cytokine efficacy testing human TLR3 protein immune function improved in vivo insight macrophage mouse model novel overexpression pathogen protein protein interaction receptor response small molecule stable cell line viral RNA

项目摘要

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) are key components of innate immunity; they serve as the first line of defense against invading pathogens such as bacteria and viruses. The signaling initiated by TLRs is a double- edged sword. On the one hand, it may lead to confining or eliminating the invading organisms; on the other hand, a prolonged and exaggerated response can cause tissue and organ damage. Moreover, TLR signaling triggered by exogenous or endogenous ligands contributes to the pathogenesis of many chronic inflammatory diseases. For example, TLR2 and TLR4 are involved in atherosclerosis, autoimmune colitis, SLE, diabetes and Alzheimer's disease. Therefore, blockade of excessive TLR signaling is a therapeutic approach being pursued for these diseases. However, currently there are no approved TLR antagonists for clinic use. A Chinese herb, Sparganium stoloniferum has long been used in Traditional Chinese Medicine (TCM) for the treatment of several inflammatory diseases. Although much work has been done with extracts from this herb, no in-depth molecular investigation of its components has been performed. Recently, in an effort to isolate and functionally characterize single compounds from Sparganium stoloniferum tubers, we identified a novel compound, Sparstolonin B (SsnB) that selectively blocks TLR2- and TLR4-mediated signaling. This R21 proposal is aimed at continuing this exciting developmental research. The central hypothesis is that SsnB can be developed as an anti-inflammatory agent by virtue of its selective inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose two specific aims. SA1. To evaluate the toxicity and the anti- inflammatory efficacy of SsnB in vivo. We will first evaluate the in vivo toxicity of SsnB and then test if SsnB can suppress the inflammatory responses in endotoxemia and sepsis mouse models. SA2. To further elucidate the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. We will identify the acting sites of SsnB on TLR2 and TLR4 signaling pathways. These studies will provide mechanistic insights into the therapeutic effects of Sparganium stoloniferum tubers in inflammatory diseases, translating a centuries-old alternative therapy modality into modern pharmacology. The identification and confirmation of SsnB as a TLR2 and TLR4 antagonist will provide an opportunity to develop a new anti-inflammatory agent. In future studies, we will test the therapeutic value of SsnB for several immune-related chronic inflammatory diseases such as atherosclerosis and diabetes. PUBLIC HEALTH RELEVANCE: There is an unmet need for the treatment of chronic inflammatory diseases. We have identified a Chinese herb-derived small molecule compound, SsnB, with selective TLR2 and TLR4 blocking activities. Elucidation of the molecular mechanism and confirmation of the in vivo anti-inflammatory activity will lead to the development of SsnB into a selective TLR2 and TLR4 antagonist and an anti-inflammatory agent.

描述（由申请人提供）：Toll样受体（TLR）是先天免疫的关键组成部分；它们是针对入侵病原体（例如细菌和病毒）的第一道防线。 TLRS发起的信号是一把双边剑。一方面，它可能导致局限或消除入侵的生物；另一方面，长时间和夸张的反应会导致组织和器官损伤。此外，由外源或内源性配体触发的TLR信号传导有助于许多慢性炎性疾病的发病机理。例如，TLR2和TLR4参与动脉粥样硬化，自身免疫性结肠炎，SLE，糖尿病和阿尔茨海默氏病。因此，过度TLR信号的阻塞是这些疾病正在采用的一种治疗方法。但是，目前尚无批准的TLR拮抗剂用于临床使用。长期以来，一种中药（TCM）用于治疗几种炎症性疾病。尽管对这种草药的提取物进行了很多工作，但未对其成分进行深入的分子研究。最近，为了隔离和功能从Sparganium stoloniferum块茎隔离单一化合物，我们确定了一种新型化合物Sparstolonin B（SSNB），该化合物有选择地阻断TLR2-和TLR4介导的信号传导。该R21提案旨在继续进行这项激动人心的发展研究。中心假设是，由于其选择性抑制作用对TLR2和TLR4信号传导，SSNB可以作为抗炎药开发。为了检验这一假设，我们提出了两个具体目标。 SA1。评估SSNB在体内的毒性和抗炎功效。我们将首先评估SSNB的体内毒性，然后测试SSNB是否可以抑制内毒素血症和败血症小鼠模型中的炎症反应。 SA2。为了进一步阐明SSNB阻止TLR2和TLR4信号传导的分子机制。我们将在TLR2和TLR4信号通路上识别SSNB的作用位点。这些研究将提供对sparganium stoloniferum块茎在炎症性疾病中的治疗作用的机理见解，将数百年历史的替代疗法模态转化为现代药理学。 SSNB作为TLR2和TLR4拮抗剂的识别和确认将为开发新的抗炎剂提供机会。在未来的研究中，我们将测试SSNB的治疗价值，以了解几种与动脉粥样硬化和糖尿病等免疫相关的慢性炎症性疾病。公共卫生相关性：对慢性炎症性疾病的治疗无需满足。我们已经确定了一种具有选择性TLR2和TLR4阻塞活性的中国草药衍生的小分子化合物SSNB。阐明分子机制和体内抗炎活性的确认将导致SSNB发展为选择性TLR2和TLR4拮抗剂和抗炎药。