title: A Synthetic Factor XIIa Inhibitor Blocks Selectively Intrinsic Coagulation Initiation.
abstract: Coagulation factor XII (FXII) inhibitors are of interest for the study of the protease in the intrinsic coagulation pathway, for the suppression of contact activation in blood coagulation assays, and they have potential application in antithrombotic therapy. However, synthetic FXII inhibitors developed to date have weak binding affinity and/or poor selectivity. Herein, we developed a peptide macrocycle that inhibits activated FXII (FXIIa) with an inhibitory constant Ki of 22 nM and a selectivity of >2000-fold over other proteases. Sequence and structure analysis revealed that one of the two macrocyclic rings of the in vitro evolved peptide mimics the combining loop of corn trypsin inhibitor, a natural protein-based inhibitor of FXIIa. The synthetic inhibitor blocked intrinsic coagulation initiation without affecting extrinsic coagulation. Furthermore, the peptide macrocycle efficiently suppressed plasma coagulation triggered by contact of blood with sample tubes and allowed specific investigation of tissue factor initiated coagulation.
authors.affiliation: †Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Baeriswyl
authors.affiliation: ‡University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital, CH-3010 Bern, Switzerland.|§Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Calzavarini
authors.affiliation: †Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Chen
authors.affiliation: †Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zorzi
authors.affiliation: ‡University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital, CH-3010 Bern, Switzerland.|§Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Bologna
authors.affiliation: ‡University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital, CH-3010 Bern, Switzerland.|§Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Angelillo-Scherrer
authors.affiliation: †Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Heinis
mesh_terms: D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D055808:Drug Discovery; D015956:Factor XIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D047028:Macrocyclic Compounds; D010455:Peptides; D015956:Factor XIIa