Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury

Yingjun Cui, Mengyi Zhang, Honglei Xu, Tingrong Zhang, Songming Zhang, Xiuhe Zhao, Peng Jiang, Jing Li*, Baijun Ye, Yuanjun Sun, Mukuo Wang, Yangping Deng, Qing Meng, Yang Liu, Qiang Fu, Jianping Lin, Liang Wang*, Yue Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the most common complications in COVID-19. Elastase has been recognized as an important target to prevent ALI/ARDS in the patient of COVID-19. Cyclotheonellazole A (CTL-A) is a natural macrocyclic peptide reported to be a potent elastase inhibitor. Herein, we completed the first total synthesis of CTL-A in 24 linear steps. The key reactions include three-component MAC reactions and two late-stage oxidations. We also provided seven CTL-A analogues and elucidated preliminary structure-activity relationships. The in vivo ALI mouse model further suggested that CTL-A alleviated acute lung injury with reductions in lung edema and pathological deterioration, which is better than sivelestat, one approved elastase inhibitor. The activity of CTL-A against elastase, along with its cellular safety and well-established synthetic route, warrants further investigation of CTL-A as a candidate against COVID-19 pathogeneses.

Original languageEnglish
Pages (from-to)2971-2987
Number of pages17
JournalJournal of Medicinal Chemistry
Volume65
Issue number4
DOIs
Publication statusPublished - 24 Feb 2022
Externally publishedYes

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