Role of LITAF in Inflammatory Disease

LITAF 在炎症性疾病中的作用

• 批准号: 9126258
• 负责人: Salomon Amar
• 金额: --
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2016-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126258
• 关键词: Adverse effects; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Atherosclerosis; Binding; Biochemical; Biological; Biological Availability; Biological Products; Blood Circulation; Blood Vessels; Bone Marrow; CCL2 gene; Cells; Cellular Assay; Clinical; Clinical Trials; Complex; Control Animal; Crohn' s disease; Cytokine Gene; Data; Defense Mechanisms; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Eicosanoids; Endotoxic Shock; Exhibits; Funding; Gene Expression; Gene Expression Regulation; Goals; Homeostasis; Human; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Inflammatory Bowel Diseases; Inflammatory Response; Injection of therapeutic agent; Injury; Insulin-Dependent Diabetes Mellitus; Interleukin-1; Interleukin-6; Investigation; Kava; Knowledge; Laboratories; Leukocytes; Libraries; Lipopolysaccharides; Marketing; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Modification; Molecular Target; Mus; Names; Natural Products; Natural regeneration; Necrosis; Nutraceutical; Oral; Outcome; Pathogenesis; Pathway interactions; Periodontal Diseases; Periodontitis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Plant Roots; Positioning Attribute; Process; Production; Property; Protein Kinase; Proteins; Rattus; Recombinant Proteins; Regulation; Research; Rheumatoid Arthritis; Role; Sepsis; Series; Signal Transduction; Signal Transduction Pathway; Site; Solubility; Structure; Survival Rate; TNF gene; Testing; Tissues; Toxic effect; United States National Institutes of Health; Variant; Vascular Endothelial Growth Factors; base; chemical stability; cost; cytokine; design; dietary supplements; experience; granulocyte; improved; in vitro activity; in vivo; inhibitor/antagonist; interest; macrophage; mouse model; novel; patient subsets; pre-clinical; programs; reactive oxygen intermediate; research clinical testing; response; scaffold; screening; small molecule; tool; transcription factor; upstream kinase

DESCRIPTION (provided by applicant): The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. In recent years the inflammatory cytokine TNF-α has been clinically validated as a primary driver of several inflammatory diseases, and biopharmaceutical drugs have been marketed that block TNF-α action. These drugs, however, are effective in only a subset of patients, and can cause severe and even fatal side effects. Moreover, because they are recombinant proteins these drugs must be administered perenterally, thus requiring repeated injections. There is a continued critical need for novel anti-inflammatory drugs that possess improved efficacy/toxicity profiles, and in particular for small molecule drugs that can be taken orally. We have recently screened a small molecule compound library in an attempt to identify compounds capable of interfering with a TNF-α transcription factor that we cloned in our laboratory 12 years ago named LITAF. The screening library, comprising in part dietary supplements and established nutraceuticals, contained at least one class of natural products that displayed TNF-α suppression activity. In particular, several compounds isolated from kava root extract were found to mediate substantial reduction of TNF-α secretion in a cellular assay. Moreover, specific kava-derived compounds were found to protect mice against lethal doses of LPS or experimental periodontitis, compared to control animals. Importantly, a representative compound from this series was shown to possess promising pharmaceutical properties including oral bioavailability in rats, and a preliminary medicinal chemistry effort has identified regions on the molecule that can be modified to optimize the compound's properties. A key objective of our over-arching research program is to identify the molecular target(s) by which kava compounds elicit their biological effect, and to elucidate their mechanism of action. However the potency of the compounds must be improved to enable these goals. The present application outlines 3 Aims: First, a comprehensive medicinal chemistry approach will be taken to design, synthesize and test compounds with the goal of delivering 2-3 biochemically well- characterized and validated tool compounds optimized for potency and for in vivo exposure. Second, these optimized, kava-derived compounds will be tested in animal models of inflammation to validate them in vivo for target identification and mechanism of action studies, and to establish their potential as a new class of anti-inflammatory drugs. Third to determine the molecular target(s) in the signal transduction pathway by which kava compounds mediate LITAF inhibition of LPS-induced cytokine secretion. Our goal is the elucidation of the mechanism of action of optimized kava compounds, a step towards identifying novel anti-inflammatory compounds suitable for clinical development.

描述（由申请人提供）：炎症反应保护机体免受感染和损伤，但其本身可能失调，对宿主产生有害后果。近年来，炎性细胞因子TNF-α已被临床验证为几种炎性疾病的主要驱动因素，并且已经上市了阻断TNF-α作用的生物制药药物。然而，这些药物仅对一部分患者有效，并且可能导致严重甚至致命的副作用。此外，由于它们是重组蛋白，这些药物必须经肠给药，因此需要重复注射。持续迫切需要具有改善的功效/毒性特征的新型抗炎药物，特别是可口服的小分子药物。我们最近筛选了一个小分子化合物库，试图鉴定能够干扰我们12年前在实验室克隆的TNF-α转录因子LITAF的化合物。筛选文库部分包括膳食补充剂和已建立的营养品，含有至少一类显示TNF-α抑制活性的天然产物。特别是，发现从卡瓦根提取物中分离的几种化合物在细胞测定中介导TNF-α分泌的显著减少。此外，与对照动物相比，特定的卡瓦衍生化合物被发现可以保护小鼠免受致死剂量的LPS或实验性牙周炎。重要的是，来自该系列的代表性化合物被证明具有有前途的药物特性，包括大鼠的口服生物利用度，并且初步的药物化学工作已经确定了分子上可以被修饰以优化化合物特性的区域。我们的过度兴奋研究计划的一个关键目标是确定卡瓦化合物引起其生物效应的分子靶点，并阐明其作用机制。然而，必须提高化合物的效力以实现这些目标。本申请概述了3个目的：首先，将采用综合药物化学方法来设计、合成和测试化合物，目的是递送2-3种生物化学上充分表征和验证的工具化合物，其针对效力和体内暴露进行了优化。其次，这些优化的卡瓦衍生化合物将在炎症动物模型中进行测试，以在体内验证它们的靶点识别和作用机制研究，并确定它们作为一类新的抗炎药物的潜力。第三，确定卡瓦化合物介导LITAF抑制LPS诱导的细胞因子分泌的信号传导途径中的分子靶点。我们的目标是阐明优化卡瓦化合物的作用机制，这是朝着确定适合临床开发的新型抗炎化合物迈出的一步。