Development of a Selective Peptide Macrocycle Inhibitor of Coagulation Factor XII toward the Generation of a Safe Antithrombotic Therapy

Abstract

Inhibition of coagulation factor XII (FXII) activity represents an attractive approach for the treatment and prevention of thrombotic diseases. The few existing FXII inhibitors suffer from low selectivity. Using phage display combined to rational design, we developed a potent inhibitor of FXII with more than 100-fold selectivity over related proteases. The highly selective peptide macrocycle is a promising candidate for the control of FXII activity in antithrombotic therapy and a valuable tool in hematology research.

A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk

“…In addition to its role in thrombosis, FXIIa initiates the inflammatory kallikrein-kinin system. The potential ability of 3F7 or peptide-based FXIIa inhibitors (49) to modulate both thrombotic (through FXI activation) and inflammatory activities (through bradykinin generation) is a distinct advantage over the aforementioned FXI inhibitors. In support of this notion is the finding that bradykinin plasma concentrations are largely elevated in patients on ECMO (50); thus, targeting FXIIa may provide an additional antiinflammatory benefit to these patients.…”

Factor XII full and partial null in rat confers robust antithrombotic efficacy with no bleeding

“…Indeed, in recent years, a multitude of inhibitors for FXII(a) have been generated and described in various preclinical models in vitro and/or in vivo. They include monoclonal antibodies [9,10], natural peptide or protein inhibitors [11,12], small molecule inhibitors [6,13], RNA aptamer [14], and antisense oligonucleotide (ASO) [15]. Although results with these various tool molecules in aggregate clearly strengthen the notion that targeting FXII may provide strong antithrombotic efficacy without conferring bleeding diathesis, some of the reagents bear the limitation of insufficient selectivity [13,16].…”

Encoded libraries of chemically modified peptides

“…In a first proof-of-principle study, bicyclic peptides of the 6 Â 6 phage display library were panned against the proteases plasma kallikrein (PK) Encoded libraries of chemically modified peptides Heinis and Winter 93 and cathepsin G, and yielded inhibitors with high affinity for both targets (K i s respectively of 1.7 and 100 nM) [14]. Bicyclic peptides were subsequently isolated to a range of other proteases such as urokinase-type plasminogen activator (uPA) [38 ] and coagulation factor XIIa [39], as well as to receptors such as Her2 [40] and Notch1.…”