Development of Selective FXIa Inhibitors Based on Cyclic Peptides and Their Application for Safe Anticoagulation

Abstract

Coagulation factor XI (FXI) has emerged as a promising target for the development of safer anticoagulation drugs that limit the risk of severe and life-threatening bleeding. Herein, we report the first cyclic peptide-based FXI inhibitor that selectively and potently inhibits activated FXI (FXIa) in human and animal blood. The cyclic peptide inhibitor (K i = 2.8 ± 0.5 nM) achieved anticoagulation effects that are comparable to that of the gold standard heparin applied at a therapeutic dose (0.3−0.7 IU/ mL in plasma) but with a substantially broader estimated therapeutic range. We extended the plasma half-life of the peptide via PEGylation and demonstrated effective FXIa inhibition over extended periods in vivo. We validated the anticoagulant effects of the PEGylated inhibitor in an ex vivo hemodialysis model with human blood. Our work shows that FXI can be selectively targeted with peptides and provides a promising candidate for the development of a safe anticoagulation therapy.

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

“…However, they lacked selectivity over trypsin. In an ex vivo hemodialysis model, the cyclic peptide PEG40-F5, an FXIa inhibitor with modest selectivity, demonstrated considerable anticoagulant activity . Obviously, peptide FXIa inhibitor development is still in its early stages, and several crucial issues, such as safety, selectivity, and PK profiles, must be addressed in the future.…”

DNA‐Encoded Libraries: Towards Harnessing their Full Power with Darwinian Evolution

“… [18–21] . The Heinis lab have recently leveraged this technology to discover potent macrocycles that inhibit activated coagulation factor XI (FXIa), a step towards safer anti‐coagulants [22] . Other approaches have been developed to further the scope of phage display libraries.…”

DNA‐Encoded Libraries: Towards Harnessing their Full Power with Darwinian Evolution

“…[18][19][20][21] The Heinis lab have recently leveraged this technology to discover potent macrocycles that inhibit activated coagulation factor XI (FXIa), a step towards safer anti-coagulants. [22] Other approaches have been developed to further the scope of phage display libraries. Bogyo and co-workers developed a method to dually cyclize and incorporate a covalent warhead into their peptide library to develop selective irreversible inhibitors of the tobacco etch virus (TEV) protease and fluorophosphonate-binding hydrolases F (FphF).…”