A novel type of facultative and plasminogen independent thrombolytic enzyme from the ancient marine organism, Sipunculus nudus

Abstract Thrombotic diseases have become a leading threat to global health, especially in the post-COVID-19 era. Current thrombolytic drugs are highly dependent on the activation of the human plasminogen. Herein we disclose a novel facultative and plasminogen independent thrombolytic enzyme (snFPITE) from Sipunculus nudus, which could completely dissolve fibrin(ogen) into ultra-small molecule fragments without leaving any undegradable D-dimer. Furthermore, it cleaves the plasminogen to form a new fibrinolytic-active agent (Flaa) rather than the conventional plasmin. Mechanistically, snFPITE activates the plasminogen and degrades fibrin(ogen) at multiple cleavage sites, and this plasminogen activation and fibrin(ogen) degradation are inhibited by plasminogen activator inhibitor 1 and α2-antiplasmin through a unique competitive inhibition mechanism. On the other hand, up to 29 snFPITE candidate sequences have been identified by mass spectroscopy, molecular cloning and genome sequencing, including 10 of which that have been functionally verified. This novel thrombolytic enzyme pool might be valuable for the rapid development of powerful and efficient thrombolytic drugs in the near future.