Study of Subglutinol A as a Potential Immunomodulatory Agent

Subglutinol A 作为潜在免疫调节剂的研究

• 批准号: 9226543
• 负责人: Jiyong Hong
• 金额: $ 26.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-09 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226543
• 关键词: Acute; Adverse effects; Affect; Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Area; Autoimmune Diseases; Autoimmune Process; Biochemical; Biological; Blood; Caring; Cell physiology; Cellular Metabolic Process; Chemicals; Chronic; Cyclosporine; Cytotoxic agent; Data; Development; Disease; Disease remission; Diterpenes; Drug Targeting; Environmental Risk Factor; Etiology; Evaluation; FK506; Future; Genetic Predisposition to Disease; Goals; Health; Immune; Immune response; Immunologics; Immunosuppressive Agents; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Investigation; Lead; Medical; Metabolic; Molecular Target; Morbidity - disease rate; Multiple Sclerosis; Natural Products; Neurologic; Outcome; Pathogenicity; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Population; Positioning Attribute; Preparation; Property; Proteomics; Pyrones; Regulation; Reporting; Research; Rheumatoid Arthritis; Risk; Safety; Series; Social Impacts; Source; Specificity; Systemic Lupus Erythematosus; T memory cell; T-Lymphocyte; Therapeutic; Toxic effect; Transplantation; Woman; analog; base; cell type; chronic autoimmune disease; clinical efficacy; design; economic impact; expectation; human disease; immunoregulation; innovation; insight; mortality; multimodality; nephrotoxicity; novel; pharmacophore; preclinical study; preference; prevent; scaffold; therapeutic target; young adult

PROJECT SUMMARY/ABSTRACT Autoimmune diseases are chronic inflammatory diseases of unknown etiology that results from the combination of genetic susceptibility, environmental factors, and immune dysregulation. There are more than 80 human diseases currently classified as autoimmune, including multiple sclerosis, inflammatory bowel diseases, type 1 diabetes mellitus, rheumatoid arthritis, and systemic lupus erythematosus. Since they affect up to 8% of the US population and often attack young adults, especially women, their social and economic impact is enormous. Immunosuppressive drugs are classical therapies to treat a wide range of autoimmune diseases. However, the treatment of autoimmune diseases has been based on non-selective immunosuppressants or cytotoxic drugs that in general offer a limited clinical efficacy. Even more selective immunosuppressive drugs such as cyclosporine A and FK506 possess serious side effects, including acute neurological toxicity and chronic nephrotoxicity. Biologicals are expensive and some patients do not respond to them adequately. Thus, efforts must be made to identify new immunomodulatory agents that are effective through a novel mechanism to circumvent existing side effects and more selective to reduce off-target effects. Subglutinols A and B are α-pyrone diterpenoid natural products with a novel chemical scaffold. They showed potent immunosuppressive activity comparable to that of cyclosporine A. We reported the first total synthesis of subglutinols A and B and demonstrated that they show multimodal immune-suppressive effects on activated T cells and possess a significant therapeutic window. We further revealed that subglutinols might exert their anti-inflammatory effects by affecting T cell metabolism which has been yet to be explored as an autoimmune disease target. All together, our data suggests that subglutinols A and B may have great potential for safe immunosuppressive therapeutics for autoimmune diseases with a novel and unique mode of action. The objective of this proposal is to identify the molecular target(s) of subglutinols to establish their mode of action and to develop subglutinol-derived chemical probes to study the regulation mechanism of immune responses through the following specific aims: (1) Identify the molecular target(s) and mode of action of sublutinols and (2) Determine the key pharmacophores of subglutinols. If successful, such therapeutics and drug targets are expected to be useful for the treatment of autoimmune diseases and for post-transplantation care, thus resulting in a sustained remission of the disease and better patient outcome.

项目摘要/摘要 自身免疫性疾病是一种原因不明的慢性炎症性疾病，由 遗传易感性、环境因素和免疫失调的组合。有更多的 目前80种人类疾病被归类为自身免疫性疾病，包括多发性硬化症、炎症性肠病 疾病、1型糖尿病、类风湿性关节炎和系统性红斑狼疮。因为它们会影响 高达8%的美国人口，经常攻击年轻人，特别是女性，他们的社会和经济 影响是巨大的。 免疫抑制药物是治疗多种自身免疫性疾病的经典疗法。 然而，自身免疫性疾病的治疗一直基于非选择性免疫抑制剂或 通常提供有限临床疗效的细胞毒性药物。更具选择性的免疫抑制药物 如环孢素A和FK506具有严重的副作用，包括急性神经毒性和 慢性肾毒性。生物制品价格昂贵，一些患者对它们没有足够的反应。因此， 必须努力确定通过新的机制有效的新的免疫调节剂 以避免现有的副作用，并更有选择性地减少偏离目标的影响。 亚谷氨酸甲酯和亚谷氨酸乙酯是一种新型化学支架的α-吡喃酮二萜类天然产物。他们 显示出与环孢菌素A相当的免疫抑制活性。我们报道了第一个 亚谷氨醇A和B的合成及其多峰免疫抑制作用的研究 激活的T细胞，并拥有一个重要的治疗窗口。我们进一步揭示了亚谷氨酸醇可能 通过影响T细胞代谢发挥抗炎作用，这一点尚未作为一种 自身免疫性疾病靶点。总而言之，我们的数据表明，亚谷氨酸醇A和B可能具有巨大的潜力 为自身免疫性疾病提供安全的免疫抑制疗法，具有新颖而独特的作用模式。 这项建议的目的是确定亚谷氨酸醇的分子靶点(S)，以建立其 作用机制，并开发亚谷氨醇衍生的化学探针来研究其调节机制 免疫应答通过以下特定目的：(1)确定分子靶点(S)和作用方式 以及(2)确定亚谷氨酸醇的关键药效团。如果成功，这种疗法和 药物靶点有望用于自身免疫性疾病的治疗和移植后。 护理，从而导致疾病的持续缓解和更好的患者结局。