Lessons from nature: engineering serine proteases for therapeutic purposes
In this public-private consortium, the Leiden University Medical Center and VarmX B.V. will join forces to engineer therapeutic serine proteases that are resistant to direct oral anticoagulants while maintaining normal functionality, with the overall goal of restoring blood coagulation in individuals treated with direct serine protease-inhibiting anticoagulants.
Thrombosis, an ‘unwanted’ blood clot, is the leading cause of mortality and morbidity in the western world, and the direct oral anticoagulants that target blood coagulation serine proteases are among the most commonly used drugs to prevent or treat thrombosis. Efficacious reversal of the anticoagulant effect of these drugs is a prerequisite for safe drug usage, which is underscored by the fact that the risk of major bleeding inherent to anticoagulant treatment is 1-3% per year, with one-in-five cases being fatal. While reversal agents have been approved for the current generation of active site-targeted direct oral anticoagulant drugs, these are lacking for the next generation of direct oral anticoagulants that is currently in development.
By introducing naturally occurring divergent structural elements that surround the active site of highly conserved chymotrypsin-like serine proteases into specific blood coagulation proteases, we aim to selectively tweak the latter in such a way that synthetic small-molecule inhibitors can no longer engage this modified active site. In contrast, the natural macromolecular substrates should still be able to engage the active site for protease-mediated catalysis. As such, normal functionality of the modified blood coagulation proteases will be preserved. Knowledge acquired on the substrate selectivity and catalytic efficiency of blood coagulation protease variants will have direct bearings on other chymotrypsin-like serine proteases, which are involved in many critical biological processes. Moreover, the novel serine protease variants will have the potential to restore hemostasis in individuals treated with direct oral anticoagulants that suffer from an adverse bleeding event or require acute surgery.
