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

doi:10.1021/acs.jmedchem.1c01583

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 journal › Article › peer-review

22 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 language	English
Pages (from-to)	2971-2987
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	4
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01583
Publication status	Published - 24 Feb 2022
Externally published	Yes

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Cui, Y., Zhang, M., Xu, H., Zhang, T., Zhang, S., Zhao, X., Jiang, P., Li, J., Ye, B., Sun, Y., Wang, M., Deng, Y., Meng, Q., Liu, Y., Fu, Q., Lin, J., Wang, L., & Chen, Y. (2022). Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury. Journal of Medicinal Chemistry, 65(4), 2971-2987. https://doi.org/10.1021/acs.jmedchem.1c01583

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

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.",

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

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Cui, Y, Zhang, M, Xu, H, Zhang, T, Zhang, S, Zhao, X, Jiang, P, Li, J, Ye, B, Sun, Y, Wang, M, Deng, Y, Meng, Q, Liu, Y, Fu, Q, Lin, J, Wang, L & Chen, Y 2022, 'Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury', Journal of Medicinal Chemistry, vol. 65, no. 4, pp. 2971-2987. https://doi.org/10.1021/acs.jmedchem.1c01583

TY - JOUR

T1 - Elastase Inhibitor Cyclotheonellazole A

T2 - Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury

AU - Cui, Yingjun

AU - Zhang, Mengyi

AU - Xu, Honglei

AU - Zhang, Tingrong

AU - Zhang, Songming

AU - Zhao, Xiuhe

AU - Jiang, Peng

AU - Li, Jing

AU - Ye, Baijun

AU - Sun, Yuanjun

AU - Wang, Mukuo

AU - Deng, Yangping

AU - Meng, Qing

AU - Liu, Yang

AU - Fu, Qiang

AU - Lin, Jianping

AU - Wang, Liang

AU - Chen, Yue

PY - 2022/2/24

Y1 - 2022/2/24

N2 - 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.

AB - 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.

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DO - 10.1021/acs.jmedchem.1c01583

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AN - SCOPUS:85123275065

SN - 0022-2623

VL - 65

SP - 2971

EP - 2987

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 4

ER -

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

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