Anti-inflammatory Natural Product Mode of Action Studies

抗炎天然产物作用模式研究

• 批准号: 7052082
• 负责人: CRAIG M CREWS
• 金额: $ 39.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052082
• 关键词: antiinflammatory agents; antineoplastics; apoptosis; binding proteins; biological products; calcium flux; chromatography; contraceptives; diterpenes; drug receptors; genetic transcription; immunosuppressive; medicinal plants; microarray technology; molecular cloning; molecular probes; nuclear factor kappa beta; pharmacokinetics; plant extracts; protein purification; protein structure function

DESCRIPTION (provided by applicant): The identification of new targets for therapeutic intervention is a major hurdle in the development of novel anti-inflammatory therapies. Fortunately, the identification of intracellular receptor proteins of biologically active natural products is yielding new targets for drug development. Recently, one promising anti-inflammatory, immunosuppressive and anti-tumor diterpene triepoxide containing natural product, triptolide, from the Chinese medicine herb Tripterygium wilfordii Hook F, has been shown to block NF-kappaB-mediated transcription. Interestingly, unlike the vast majority of anti-inflammatory agents, triptolide does not inhibit NFkappaB nuclear translocation or DNA binding but rather inhibits its transcriptional activating ability. The mechanism for this unique mode of NF-kappaB inhibition remains unknown. Taking a multi-disciplinary approach, we propose to explore the molecular mechanisms of triptolide's antiinflammatory and anti-proliferative activity through the purification and characterization of triptolide-binding proteins. A careful biological/biochemical validation of these triptolide binding activities will greatly aid our understanding of triptolide's potent anti-inflammatory effects and in the basic biology of NF-kappaB transcriptional activation. In addition, this information and that gained from the further exploration of the triptolide-sensitive inflammatory signaling pathway(s) may provide the basis for the development of novel anti-inflammatory, immunosuppressive and anti-proliferative drugs.

描述（由申请人提供）：治疗干预新靶点的识别是开发新型抗炎疗法的主要障碍。幸运的是，生物活性天然产物的细胞内受体蛋白的鉴定正在为药物开发提供新的靶标。最近，一种有前景的抗炎、免疫抑制和抗肿瘤二萜三环氧化物，含有来自中药雷公藤中的天然产物雷公藤甲素，已被证明可以阻断 NF-κB 介导的转录。有趣的是，与绝大多数抗炎药不同，雷公藤甲素不会抑制 NFkappaB 核转位或 DNA 结合，而是抑制其转录激活能力。这种独特的 NF-κB 抑制模式的机制仍不清楚。 采用多学科方法，我们建议通过雷公藤甲素结合蛋白的纯化和表征来探索雷公藤甲素抗炎和抗增殖活性的分子机制。对这些雷公藤内酯醇结合活性进行仔细的生物学/生化验证将极大地帮助我们了解雷公藤内酯醇的有效抗炎作用以及 NF-kappaB 转录激活的基础生物学。此外，这些信息以及从雷公藤甲素敏感炎症信号通路的进一步探索中获得的信息可能为开发新型抗炎、免疫抑制和抗增殖药物提供基础。