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 (<i>K</i>_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 <i>via</i> PEGylation and demonstrated effective FXIa inhibition over extended periods <i>in vivo</i>. We validated the anticoagulant effects of the PEGylated inhibitor in an <i>ex vivo</i> 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.