Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming

The contact system comprises a series of serine proteases that mediate procoagulant and proinflammatory activities via the intrinsic pathway coagulation kallikrein–kinin system, respectively. Inhibition Factor XIIa (FXIIa), an initiator has been demonstrated to lead thrombo-protection anti-inflammatory effects in animal models serves as potentially safer target for development antithrombotics. Herein, we describe use Randomised Nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology identify potent selective cyclic peptide inhibitors FXIIa. Cyclic peptides were evaluated vitro, three compounds exhibited significant prolongation aPTT, reduction thrombin generation, inhibition bradykinin formation. We also our efforts critical residues binding FXIIa through alanine scanning, analogue silico methods predict mode inhibitors.