Study of Subglutinol A as a Potential Immunomodulatory Agent

Subglutinol A 作为潜在免疫调节剂的研究

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要自身免疫性疾病是一种病因不明的慢性炎症性疾病，由自身免疫性疾病引起。遗传易感性、环境因素、免疫失调等综合因素较多。目前被归类为自身免疫性疾病的 80 种人类疾病，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，尤其是女性，影响他们的社会和经济状况影响是巨大的。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细胞毒性药物通常提供有限的临床疗效，甚至更具选择性的免疫抑制药物。环孢素A和FK506等药物具有严重的副作用，包括急性神经毒性和慢性肾毒性。生物制剂价格昂贵，并且一些患者对其反应不充分。必须通过新机制来识别有效的新免疫调节剂规避现有的副作用，并更有选择性地减少脱靶效应。 Subgluinols A 和 B 是具有新型化学支架的 α-吡喃酮二萜类天然产物。显示出与环孢菌素 A 相当的有效免疫抑制活性。我们报告了第一个总的合成了 subglutinols A 和 B，并证明它们对人体表现出多模式免疫抑制作用我们进一步揭示了 subgluinols 可能会激活 T 细胞并具有显着的治疗窗口。通过影响 T 细胞代谢发挥抗炎作用，这一点尚未被探索为总而言之，我们的数据表明，亚粘醇 A 和 B 可能具有巨大的潜力。以新颖且独特的作用方式为自身免疫性疾病提供安全的免疫抑制疗法。该提案的目的是确定亚粘醇的分子靶标，以确定其作用方式并开发亚凝醇衍生的化学探针来研究其调节机制免疫反应通过以下具体目标：（1）确定分子靶点和作用方式 (2) 确定 subglutinols 的关键药效团如果成功，此类疗法和药物靶点预计可用于治疗自身免疫性疾病和移植后护理，从而实现疾病的持续缓解和更好的患者预后。