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.

Peptide Human Neutrophil Elastase Inhibitors from Natural Sources: An Overview

“…Moreover, they tested the synthesized Cyclotheonellazole A against human neutrophil elastase, showing an IC 50 value of 0.321 µM. Therefore, they proved that this compound is a more effective inhibitor against elastase than sivelestat (IC 50 = 0.704 µM), showing an inconsistent result compared with the previous study conducted by Issac et al; this is probably due to different experimental conditions, such as the source and concentration of the enzyme, the substrate and the time of incubation [ 45 , 46 ]. Elastase has recently been considered as a potential target for the prevention of ARDS in patients afflicted with SARS2-CoV-2 infection [ 14 ].…”

“…Elastase has recently been considered as a potential target for the prevention of ARDS in patients afflicted with SARS2-CoV-2 infection [ 14 ]. The high elastase inhibitory activity of this compound could be particularly advantageous for patients with a D614G genotype infection [ 46 ].…”

Sivelestat improves clinical outcomes and decreases ventilator-associated lung injury in children with acute respiratory distress syndrome: a retrospective cohort study

“…However, the overexpression of neutrophil elastase, which is a protease enzyme, is one of the main factors of lung consolidation and dysfunctional oxygenation in ARDS patients. Sivelestat, a neutrophil elastase inhibitor, reduces elastase activation and inhibits neutrophil aggregation by reducing the inflammatory response and the concentrations of IL-8 and tumor necrosis factor-α (TNF-α) (29)(30)(31). Numerous studies have concluded that sivelestat is therapeutically effective in treating ARDS, organ transplantation, tumors, and trauma (29,30,32).…”

Advances Toward COVID-19 Therapies Special Issue

“…Cui et al describe the first total synthesis of cyclotheonellazole A, a natural macrocyclic peptide elastase inhibitor, in 24 linear steps. 19 Ashhurst et al show that the marine natural product, gallinamide A, and several synthetic analogues are potent inhibitors of cathepsin L, a key host cysteine protease important for viral entry. 20 Gallinamide A directly interacts with cathepsin L in cells and potently inhibits SARS-CoV-2 infection in the nanomolar range.…”

“…Elastase is a serine protease that is mainly expressed on neutrophils and is an important cellular target to prevent acute lung injury/acute respiratory distress syndrome in COVID-19 patients. Cui et al describe the first total synthesis of cyclotheonellazole A, a natural macrocyclic peptide elastase inhibitor, in 24 linear steps . Ashhurst et al show that the marine natural product, gallinamide A, and several synthetic analogues are potent inhibitors of cathepsin L, a key host cysteine protease important for viral entry .…”