Discovery of potent antiosteoporotic cyclic depsipeptides with an unusual nitrile hydroxy acid from Microascus croci

Shasha Li; Yining Li; Ting Yu; Xinwei Wei; Yuyan Zhang; Bo Chen; Shuyi Si; Yanni Xu; Maoluo Gan

doi:10.1016/j.bioorg.2025.108133

Discovery of potent antiosteoporotic cyclic depsipeptides with an unusual nitrile hydroxy acid from Microascus croci

Bioorg Chem. 2025 Jan 5:155:108133. doi: 10.1016/j.bioorg.2025.108133. Online ahead of print.

Authors

Shasha Li¹, Yining Li², Ting Yu¹, Xinwei Wei², Yuyan Zhang², Bo Chen¹, Shuyi Si², Yanni Xu³, Maoluo Gan⁴

Affiliations

¹ National Center for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
² National Center for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
³ National Center for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: [email protected].
⁴ National Center for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: [email protected].

PMID: 39798453
DOI: 10.1016/j.bioorg.2025.108133

Abstract

Two cyclic octadepsipeptides, microascusins A and B (1 and 2), were identified from the marine sponge-associated Microascus croci IMB19-064 co-cultivated with Escherichia coli. Their structures and conformations in solution were determined by comprehensive spectroscopic data analysis. The absolute configurations of amino and hydroxy acids were determined by the advanced Marfey's and O-Marfey's methods, respectively, as well as chiral-phase HPLC analysis. Microascusins A (1) and B (2) represent a new type of cyclic octadepsipeptides characterized by the presence of the unique hydroxy acid l-2-hydroxy-4-cyanobutyric acid. Compound 1 exhibited potent in vitro antiosteoporotic activity with dual regulation effects of promoting the osteoblast-mediated bone formation as well as inhibiting the RANKL-induced osteoclast differentiation at the concentrations of 0.1-10 nM. Further in vivo study showed that compound 1 could improve bone mineralization after dexamethasone-induced bone damage in zebrafish through up-regulating the expression of the osteoblast-specific genes Bmp2 and Oc.

Keywords: Antiosteoporosis; Co-cultivation; Cyclic depsipeptide; Microascus croci; Sponge-associated fungus.