SsnB, a Chinese herb-derived selective TLR antagonist

SsnB，一种中药来源的选择性 TLR 拮抗剂

• 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
• 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' 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

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;它们作为抵御入侵病原体（如细菌和病毒）的第一道防线。TLR启动的信号传导是一把双刃剑.一方面，它可能导致限制或消除入侵的生物体;另一方面，长时间和过度的反应可能导致组织和器官损伤。此外，由外源性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制。例如，TLR 2和TLR 4参与动脉粥样硬化、自身免疫性结肠炎、SLE、糖尿病和阿尔茨海默病。因此，阻断过度TLR信号传导是这些疾病的治疗方法。然而，目前没有批准的TLR拮抗剂用于临床使用。黑三棱是一种中草药，长期以来一直用于传统中医（TCM）治疗几种炎症性疾病。虽然已经做了大量的工作，从这种草药提取物，没有深入的分子研究其成分已被执行。最近，在努力分离和功能特性的单一化合物从三棱块茎，我们确定了一种新的化合物，Sparstolonin B（SsnB），选择性地阻断TLR 2和TLR 4介导的信号。这项R21提案旨在继续这项令人兴奋的发展研究。中心假设是，SsnB可以凭借其对TLR 2和TLR 4信号传导的选择性抑制作用而被开发为抗炎剂。为了验证这一假设，我们提出了两个具体目标。SA 1.评价SsnB的体内毒性和抗炎作用.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脓毒症小鼠模型中的炎症反应。SA 2.进一步阐明SsnB阻断TLR 2和TLR 4信号传导的分子机制。我们将确定SsnB在TLR 2和TLR 4信号通路上的作用位点。这些研究将为三棱块茎在炎症性疾病中的治疗作用提供机制见解，将一种有数百年历史的替代治疗方式转化为现代药理学。SsnB作为TLR 2和TLR 4拮抗剂的鉴定和确认将为开发新的抗炎药物提供机会。在未来的研究中，我们将测试SsnB对几种免疫相关慢性炎症性疾病如动脉粥样硬化和糖尿病的治疗价值。 公共卫生相关性：慢性炎症性疾病的治疗需求尚未得到满足。我们已经确定了一种中药衍生的小分子化合物，SsnB，具有选择性TLR 2和TLR 4阻断活性。阐明SsnB的分子机制并确认其体内抗炎活性将导致SsnB发展为选择性TLR 2和TLR 4拮抗剂和抗炎剂。