Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and In Vivo Biological Evaluation for Acute Lung Injury.
J Med Chem
; 65(4): 2971-2987, 2022 02 24.
Article
in English
| MEDLINE | ID: covidwho-1616927
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Peptides, Cyclic
/
Respiratory Distress Syndrome
/
Serine Proteinase Inhibitors
/
Leukocyte Elastase
/
Acute Lung Injury
Type of study:
Experimental Studies
Limits:
Animals
/
Humans
/
Male
Language:
English
Journal:
J Med Chem
Journal subject:
Chemistry
Year:
2022
Document Type:
Article
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