新型免疫抑制剂brasilicardin A的研究进展

Advances of the novel immunosuppressant brasilicardin A

摘要:

Brasilicardin A (BraA)是从致病性放线菌巴西诺卡菌(Nocardia brasiliensis) IFM 0406中发现的具有显著免疫抑制作用(IC₅₀=0.057μg/mL)的二萜糖苷类化合物。BraA发挥免疫抑制活性的作用机制与现有临床常用的免疫抑制剂不同，BraA通过抑制氨基酸转运体L系统的转运进而影响T-淋巴细胞对氨基酸的摄入而发挥免疫抑制作用。相比目前已知的免疫抑制剂环孢菌素A、子囊霉素和他克莫司等，BraA在小鼠混合淋巴细胞反应中显示低毒、高效的优势。因此，BraA作为新型的免疫抑制剂，极具开发潜力，已成为全球免疫抑制剂发现新领域。但其结构复杂、合成困难，原菌种产率低且具有致病性，BraA及其类似物的获得已成为此类新型免疫抑制剂研究的瓶颈。本文综述了BraA的分子特征、药理活性、作用机制、目前获得的BraA类似物和衍生化方面的研究进展，以期为BraA及其类似物的高效生产提供参考。

Abstract:

Brasilicardin A (BraA) is a natural diterpene glycoside isolated from the pathogenic actinomycete Nocardia brasiliensis IFM 0406 with highly potent immunosuppressive activity (IC₅₀=0.057 μg/mL). BraA potently inhibits the uptake of amino acids that are substrates for amino acid transport system L of T cells, which is different from the existing clinical immunosuppressants. BraA is more potent in a mouse mixed lymphocyte reaction and less toxic against various human cell lines compared with the known clinical immunosuppressants, such as cyclosporin A, ascomycin and tacrolimus. Therefore, BraA attracted more attention as a new promising immunosuppressant. However, the development of this promising immunosuppressant as drug for medical use is so far hindered because BraA has the unusual and synthetically challenging skeleton and shows the low-yield production in the natural pathogenic producer. This review introduces the molecular structure of BraA, its activity, mechanism of action, chemical synthesis of BraA analogs, heterologous expression of gene cluster, and an application of combining microbial and chemical synthesis for production of BraA, with the aim to facilitate the efficient production of BraA and its analogs.