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Engineering a Plasmin Inhibitor♦

Serine proteases are involved in many physiological processes, among them blood coagulation and fibrinolysis. Serine protease activity is tightly regulated by inhibitors, an interaction that can be exploited for therapeutic use; for example, bovine basic pancreatic trypsin inhibitor (BPTI) has been used to reduce blood loss during surgery, but risks associated with its bovine origin have resulted in its removal from clinical use. Although humans don’t have a BPTI homolog, they do have several proteins with BPTI-like domains, so in this Paper of the Week, Madhu Bajaj and colleagues used structure-based approaches to engineer the Kunitz domain 1 of the protein TFPI-2 as a fibrinolysis inhibitor. Their analysis suggested that a simple leucine to arginine change at residue 17 would abolish KD1’s coagulant properties while enhancing antifibrolytic function; at the same time a minimal change would minimize any risks of an immune response in humans. Using a mouse model, Bajaj and colleagues showed that KD1L17R was more effective than WT KD1 and, importantly, BPTI, in inhibiting plasmin and preventing blood loss from liver laceration, and no renal toxicity was observed. All in all, this engineered protein displayed stability, high selectivity, and no toxicity, a trifecta that suggests tremendous potential as the basis for developing therapeutics.