Defining the Mechanism of Action of Sanglifehrin A

定义 Sanglifehrin A 的作用机制

• 批准号: 7878663
• 负责人: Dylan T. Stiles
• 金额: $ 4.76万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878663
• 关键词: Anabolism; Autoimmune Diseases; Biological; Biotin; Cell Extracts; Complex; Cyclophilin A; Engineering; FK506; Graft Rejection; Health; Human; Immune system; Immunosuppressive Agents; Incubated; Light; Medicine; Organ Transplantation; Proteins; Research; Signal Transduction Pathway; Sirolimus; Structure; T-Cell Activation; Testing; Therapeutic Agents; Work; base; improved; insight; member; novel; novel therapeutics; public health relevance; sanglifehrin A; scaffold

DESCRIPTION (provided by applicant): Sanglifehrin A (SFA) is a recently discovered natural compound that has strong biological activity as an immunosuppressant, making it potentially useful in the treatment of organ transplant rejection and various autoimmune diseases. The precise mechanism by which SFA operates is not known, but it appears to function in a manner distinctly different from other immunosuppressants such as FK506 and rapamycin. Preliminary studies have shown that that SFA forms a complex with cyclophilin A (CypA), which then acts on an unknown target(s). The working hypothesis of this proposal is that SFA acts on a previously unknown member of the signal transduction pathway leading to T cell activation. This hypothesis will be tested by: (1) sequencing a BAG clone containing the SFA biosynthetic cluster to obtain insights into the biosynthesis of the molecule; (2) preparing a biotin-tagged SFA derivative; and (3) incubating the biotinylated probe with a cell extract, then purifying and analyzing the protein mixture to identify the target of SFA (TOS). Identifying the biological target of the SFA-CypA complex will shed light on the mechanism of action of this novel immunosuppressant and enrich our understanding of the immune system. In long-term research based on this work, the structure of SFA may well present a new scaffold upon which to engineer biological probes to study the immune system and improve human health. PUBLIC HEALTH RELEVANCE: Sanglifehrin A (SFA) is a recently discovered natural compound that has strong biological activity as an immunosuppressant, making it potentially useful in the treatment of organ transplant rejection and various autoimmune diseases. Little is known about how SFA operates in the body, but it appears to have an activity distinctly different from other immunosuppressants currently used in medicine. This study aims to elucidate the mechanism by which SFA functions, enriching our understanding of the immune system and this novel therapeutic agent.

描述（申请人提供）：Sanglifehrin A（SFA）是最近发现的一种天然化合物，作为免疫抑制剂具有很强的生物活性，使其在治疗器官移植排斥和各种自身免疫性疾病方面具有潜在的用途。 SFA 起作用的确切机制尚不清楚，但它的作用方式似乎与 FK506 和雷帕霉素等其他免疫抑制剂明显不同。初步研究表明，SFA 与亲环蛋白 A (CypA) 形成复合物，然后作用于未知靶标。该提案的工作假设是，SFA 作用于信号转导途径中先前未知的成员，导致 T 细胞激活。该假设将通过以下方式进行检验：（1）对包含 SFA 生物合成簇的 BAG 克隆进行测序，以深入了解该分子的生物合成； (2)制备生物素标记的SFA衍生物； (3)将生物素化探针与细胞提取物一起孵育，然后纯化并分析蛋白质混合物以鉴定SFA (TOS)的靶标。识别 SFA-CypA 复合物的生物学靶点将有助于阐明这种新型免疫抑制剂的作用机制，并丰富我们对免疫系统的理解。在基于这项工作的长期研究中，SFA的结构很可能提供一种新的支架，可以在其上设计生物探针来研究免疫系统和改善人类健康。公共健康相关性：Sanglifehrin A (SFA) 是一种最近发现的天然化合物，作为免疫抑制剂具有很强的生物活性，使其可能用于治疗器官移植排斥和各种自身免疫性疾病。人们对 SFA 如何在体内发挥作用知之甚少，但它的活性似乎与目前医学上使用的其他免疫抑制剂明显不同。本研究旨在阐明 SFA 的作用机制，丰富我们对免疫系统和这种新型治疗剂的理解。