**4. Conclusions**

In summary, our chemical exploratory investigations on the mangrove-derived endophytic fungus *Phomopsis asparagi* DHS-48 led to the characterization of three new cytochalasins and five known analogs. Phomoparagin A (**1**) represents the first example of a cytochalasan that features an unprecedented 5/6/5/8/5-fused pentacyclic skeleton, and phomoparagin B (**2**) of the CN-NFAT signaling pathway was discovered and is a promising immunosuppressant, as it directly inhibited calcineurin and did not require a matchmaker protein, such as the clinical immunosuppressants CsA and FK506. The potent immunosuppressive activity and low toxicity of **2** collectively suggested that it is an attractive option for immunosuppressive drug development.

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/md20080526/s1.

**Author Contributions:** J.X. designed and supervised this research, structure elucidation, wrote the draft and final revision of the manuscript. Z.F. and C.W. performed the isolation. X.Z. and D.Z. carried out the biological evaluation. J.W. carried out the molecular docking. T.F. performed the HPLC analysis. Z.W. measured the NMR spectra. The final revision of the manuscript was revised by all the authors. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the National Natural Science Foundation of China (No. 82160675/81973229), Key Science and Technology Project of Hainan Province (ZDKJ202008/ ZDKJ202018) and Key Research Program of Hainan Province (ZDYF2021SHFZ108) and Guangdong Key Laboratory of Marine Materia Medica Open Fund (LMM2021-4) are gratefully acknowledged.

**Institutional Review Board Statement:** All experiments conducted on animal material were approved by the Ethics Committee of the Hainan University (HNUAUCC-2021-00082, 17 February 2021), and all methods used were compliant with the regulations of the Ethics Committee.

**Conflicts of Interest:** The authors declare no conflict of interest.
