Total synthesis and biological evaluation of Lyngbyastatin 7 for the treatment of pulmonary diseases

Lyngbyastatin 7 is marine-derived cyanobacterial cyclodepsipeptide that showed better potency towards inhibiting elastase than sivelestat, the only approved drug targeting this enzyme. The discovery of elastase inhibitors is of great importance since this enzyme plays a significant role in several pulmonary diseases, such as chronic obstructive pulmonary disease, the third leading cause of death worldwide. We established the first total synthesis of lyngbyastatin 7 and validated the elastase-inhibitory activity in enzyme assays. Lyngbyastatin 7 also outperformed sivelestat in our cellular assays, where the compound protected human bronchial epithelial cells against elastase-induced antiproliferative effects as well as attenuated the transcription of sICAM-1 and IL1β which are induced by elastase. The synthetic accessibility overcomes the supply issue and paves the way for the synthesis of diverse analogues with the goal of discovering effective therapeutics against elastase-mediated pathologies.