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（Acute lung injury/acute respiratory distress syndrome, ALI/ARDS）是新型冠状病毒感染（COVID-19）最常见的并发症之一。弹性蛋白酶（elastase）被认为是防治新冠患者ALI/ARDS的重要靶点。环索奈唑A（Cyclotheonellazole A, CTL-A）是一种天然大环肽类化合物，据报道为强效弹性蛋白酶抑制剂。本文首次通过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。本研究同时合成了7种CTL-A类似物，并阐明了其初步的构效关系。体内ALI小鼠模型实验进一步证实，CTL-A可通过减轻肺水肿与病理恶化缓解急性肺损伤，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、良好的细胞安全性及成熟的合成路线，因此其作为新型冠状病毒感染病理进程防治候选药物的潜力值得进一步研究。