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

  • J Med Chem. 2022 Feb 24;65(4):2971-2987. doi: 10.1021/acs.jmedchem.1c01583.
Yingjun Cui  1 ,  Mengyi Zhang  1 ,  Honglei Xu  1 ,  Tingrong Zhang  1 ,  Songming Zhang  1 ,  Xiuhe Zhao  1 ,  Peng Jiang  1 ,  Jing Li  1  2 ,  Baijun Ye  1 ,  Yuanjun Sun  1 ,  Mukuo Wang  1 ,  Yangping Deng  2 ,  Qing Meng  1 ,  Yang Liu  1 ,  Qiang Fu  3 ,  Jianping Lin  1  4 ,  Liang Wang  1  2 ,  Yue Chen  1  2
Affiliations
  • 1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300353, People's Republic of China.
  • 2. College of Chemistry, Nankai University, Tianjin 300071, People's Republic of China.
  • 3. Tianjin 4th Centre Hospital, Tianjin 300140, People's Republic of China.
  • 4. Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, People's Republic of China.
PMID: 35005973 DOI: 10.1021/acs.jmedchem.1c01583
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.

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