Study of Subglutinol A as a Potential Immunomodulatory Agent

项目总结/摘要 自身免疫性疾病是病因不明的慢性炎症性疾病，由以下原因引起： 遗传易感性、环境因素和免疫失调的组合。有超过 80种人类疾病目前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。因为它们影响 高达8%的美国人口，经常攻击年轻人，特别是妇女，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免疫抑制剂。 细胞毒性药物通常提供有限的临床功效。更有选择性的免疫抑制药物 如环孢素A和FK 506具有严重的副作用，包括急性神经毒性， 慢性肾毒性生物制剂价格昂贵，有些病人对它们没有充分的反应。因此，在本发明中， 必须努力鉴定通过新机制有效的新免疫调节剂 以避免现有的副作用，并更具选择性以减少脱靶效应。 辛香醇A和辛香醇B是具有新型化学骨架的α-吡喃酮二萜类天然产物。他们 显示出与环孢菌素A相当的有效免疫抑制活性。我们报告了第一个总数 合成了亚甲基二醇A和B，并证明了它们显示多模式免疫抑制作用， 活化的T细胞，并具有显著的治疗窗口。我们进一步发现， 通过影响T细胞代谢发挥其抗炎作用， 自身免疫性疾病靶点。总的来说，我们的数据表明，亚醇A和B可能具有很大的潜力 用于自身免疫性疾病的安全的免疫抑制治疗剂，其具有新颖且独特的作用模式。 该提案的目的是确定subtichols的分子靶点，以建立其 的作用方式，并开发辛二醇衍生的化学探针，以研究调节机制， 免疫应答通过以下具体目标：（1）识别分子靶标和作用模式 （2）确定sublutinols的关键药效团。如果成功，这种治疗方法和 预期药物靶点可用于治疗自身免疫性疾病和用于移植后 护理，从而导致疾病的持续缓解和更好的患者结局。

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.