A Novel Derivative of (-)mycousnine Produced by the Endophytic Fungus Mycosphaerella nawae, Exhibits High and Selective Immunosuppressive Activity on T Cells

• Main Authors: Li-Wei Wang, Jin-Liang Wang, Jing Chen, Jia-Jie Chen, Jia-Wei Shen, Xiao-Xiao Feng, Christian P. Kubicek, Fu-Cheng Lin, Chu-Long Zhang, Feng-Yang Chen
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2017-07-01
• Series: Frontiers in Microbiology
• Subjects: Mycosphaerella nawae; (-)mycousnine enamine; dibenzofurane; T-cell targeting; immunosuppressive activity
• Online Access: http://journal.frontiersin.org/article/10.3389/fmicb.2017.01251/full

An endophytic fungus, Mycosphaerella nawae ZJLQ129, was isolated from the leaves of the traditional Chinese medicine Smilax china. From the fermentation broth and mycelium, a dibenzofurane compound (-)mycousnine (1) was isolated. Chemical modification of it to the amide derivative (-)mycousnine enamine (2), which is new to science, was found to have high and selective immunosuppressive activity: similar to cyclosporin A, (-)mycousnine enamine (2) selectively inhibited T cell proliferation, suppressed the expression of the surface activation antigens CD25 and CD69 and the formation and expression of the cytokines interleukin-2 as well as interferon γ in activated T cells, but did not show any effect on the proliferation of B cells and cancer cells (PANC-1 and A549) and the activation of macrophages. Furthermore, the cytotoxicity of (-)mycousnine enamine was lower than that of cyclosporin A, and its therapeutic index (TC50/EC50) was 4,463.5, which is five-fold higher than that of cyclosporin A. We conclude that (-)mycousnine enamine (2), the semi-synthestic product prepared from the native product (-)mycousnine (1) of the endophyte M. nawae is a novel effective immunosuppressant showing low toxicity and high selectivity.