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.

急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是新型冠状病毒肺炎（COVID-19）最常见的并发症之一。弹性蛋白酶（Elastase）已被证实是预防COVID-19患者发生ALI/ARDS的重要靶点。环噻唑霉素A（CTL-A）是一种天然大环肽（natural macrocyclic peptide），据报道为强效弹性蛋白酶抑制剂。本研究首次通过24步线性合成完成了CTL-A的全合成，关键反应包括三组分MAC反应与两步后期氧化反应。此外，我们合成了7种CTL-A类似物，并阐明了初步的构效关系。体内ALI小鼠模型实验进一步表明，CTL-A可通过减轻肺水肿与缓解病理恶化改善急性肺损伤，其效果优于已获批的弹性蛋白酶抑制剂西维来司他（sivelestat）。CTL-A具备抗弹性蛋白酶活性、良好的细胞安全性以及成熟的合成路线，有必要进一步探究其作为抗COVID-19发病机制候选药物的潜力。