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

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.