Plasminogen (Plg) is the zymogen of serine protease plasmin (Plm) which plays a key role in fibrin dissolution, tissue remodeling and wound healing. Therefore, it is an attractive therapeutic target for a range of different medical conditions, e.g. traumatic bleeding, thrombosis and cancer. Plasmin inhibition is crucial to overcome undesirable plasmin activity, predominantly excessing blood loss. Currently, Plm inhibitors, also known as anti-fibrinolytic agents, lack either specificity (cross react with other serine proteases such as Aprotinin) or efficacy (weak binding to active pocket such as YO-2). Therefore, the search for a specific and efficacious Plm inhibitor is an ongoing research effort in the field.
Sunflower trypsin inhibitor-1 (SFTI-1) is a 14-amino-acid cyclic peptide that is well known for its exceptional stability and potency for trypsin (Ki=100 pM).It is therefore a very promising drug scaffold for developing specific inhibitors of serine proteases. Here, we determined the molecular interactions between SFTI-1 variants and Plm, with the aim to use a structure-based drug design approach to accelerate the process. We report the high-resolution x-ray crystal structures of catalytic domain of Plm (mPlm) in complex with SFTI-1 variants and show how the P2 and P2’ are critical for the potency of the inhibitor. This work forms the bases for future development of specific Plm inhibitors that might be of great values in the management of bleeding, also cell metastasis, angiogenesis and cell proliferation.