Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity
Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity
复制标题
DOI：
10.1021/acs.jnatprod.9b00144
复制
发表时间：
2019-08-01
影响因子：
5.1
通讯作者：
Yoon, Yeo Joon
中科院分区：
文献类型：
--
作者：
Beom, Ji Yoon;Jung, Jin A.;Yoon, Yeo Joon
降低FK506(1)的强烈免疫抑制活性对于开发这种化合物作为抗真菌药物是必不可少的。在FK506结合蛋白12-和钙调神经磷酸酶结合区都进行了修饰，合成了7个新的FK506类似物。9-DeoxoFK520(7)在体外免疫抑制活性降低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。7与氟康唑表现出较强的协同抗真菌活性。FK506(1)是一种由几种链霉菌产生的23元大环内酯类化合物，用于预防移植器官的排斥反应。FK506还表现出抗真菌、神经保护和神经再生活性。在人类中，FK506与FK506结合蛋白(FKBP)12结合，得到的FKBP12-FK506复合体与钙依赖的钙调蛋白磷酸酶钙调神经磷酸酶(CaN)相互作用。通过形成FKBP12-FIC506-CaN三元复合体使CaN失活，可阻止活化T细胞核因子(NF-AT)的激活，从而抑制IL-2的产生和随后的T细胞增殖。该CaN信号通路在新生隐球菌、白色念珠菌、烟曲霉等主要真菌病原体的生长和致病过程中也起着重要作用。因此，合成能够区分人类FKBP12/CAN和其真菌类似物的FK506类似物可能会将抗真菌活性与免疫抑制活性分开，从而使新型抗真菌药物的开发成为可能。
A reduction in the strong immunosuppressive activity of FK506 (1) 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 (7) exhibited a >900-fold reduction in the in vitro 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. 7 exhibited robust synergistic antifungal activity with fluconazole. FK506 (1) is a 23-membered macrolide produced by several Streptomyces 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 Ca2+-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FIC506-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 Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. 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.