Department of Chemistry and Nanoscience , Ewha Womans University , Seoul 03760 , Republic of Korea.
Department of Biotechnology, College of Life Science and Biotechnology , Yonsei University , Seoul 03722 , Republic of Korea.
J Nat Prod. 2019 Aug 23;82(8):2078-2086. doi: 10.1021/acs.jnatprod.9b00144. Epub 2019 Jul 19.
A reduction in the strong immunosuppressive activity of FK506 () is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 () exhibited a >900-fold reduction in the immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. exhibited robust synergistic antifungal activity with fluconazole. FK506 () is a 23-membered macrolide produced by several species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FK506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as , , and . Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.
降低 FK506（他克莫司）的强免疫抑制活性对于将该化合物开发为抗真菌剂至关重要。生物合成了 7 种在 FK506 结合蛋白 12 和钙调神经磷酸酶结合区域均进行修饰的新型 FK506 类似物。9-去氧 FK520（）的免疫抑制活性降低了 >900 倍，但仍保持显著的抗真菌活性，表明 C-9 和 C-21 位对于分离免疫抑制和抗真菌活性至关重要。与氟康唑联合使用时表现出强大的协同抗真菌活性。FK506（他克莫司）是由几种 产生的 23 元大环内酯类化合物，用作免疫抑制剂以防止移植器官的排斥。FK506 还表现出抗真菌、神经保护和神经再生活性。在人体内，FK506 与 FK506 结合蛋白（FKBP）12 结合，形成的 FKBP12-FK506 复合物与钙调神经磷酸酶（CaN）的钙调蛋白依赖性磷酸酶相互作用。通过形成 FKBP12-FK506-CaN 三元复合物使 CaN 失活可防止活化 T 细胞核因子（NF-AT）的激活，从而抑制白细胞介素-2 的产生和随后的 T 细胞增殖。该 CaN 信号通路在主要真菌病原体如 、 和 的生长和发病机制中也起着至关重要的作用。因此，合成能够区分人 FKBP12/CaN 与其真菌对应物的 FK506 类似物，可能将抗真菌活性与免疫抑制活性分离，从而开发出新型抗真菌药物。
