title: Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity.
abstract: Factor XII (FXII) is a plasma protease that has emerged in recent years as a potential target to treat or prevent pathological thrombosis, to inhibit contact activation in extracorporeal circulation, and to treat the swelling disorder hereditary angioedema. While several protein based inhibitors with high affinity for activated FXII (FXIIa) were developed, the generation of small molecule inhibitors has been challenging. In this work, we have generated a potent and selective FXIIa inhibitor by optimizing a peptide macrocycle that was recently evolved by phage display (Ki= 0.84 ± 0.03 nM). A fluorine atom introduced in the para-position of phenylalanine enhanced the binding affinity as much as 10-fold. Furthermore, we improved the proteolytic stability by substituting the N-terminal arginine by norarginine. The resulting inhibitor combines high inhibitory affinity and selectivity with a good stability in plasma (Ki= 1.63 ± 0.18 nM, >27 000-fold selectivity, t1/2(plasma) =16 ± 4 h). The inhibitor efficiently blocked activation of the intrinsic coagulation pathway in human blood ex vivo.
authors.affiliation: Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH-1015 Lausanne, Switzerland.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Middendorp
authors.affiliation: Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH-1015 Lausanne, Switzerland.
authors.forename: Jonas
authors.initials: J
authors.lastname: Wilbs
authors.affiliation: University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, University of Bern, Inselspital, CH-3010 Bern, Switzerland.|Department of Clinical Research, University of Bern , CH-3010 Bern, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Quarroz
authors.affiliation: University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, 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: University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, 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.identifier: 0000-0001-9982-9457
authors.initials: C
authors.lastname: Heinis
mesh_terms: D005174:Factor XII / Q000037:antagonists & inhibitors*; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*; D059748:Proteolysis
chemical_list: D047028:Macrocyclic Compounds; D010455:Peptides; D005174:Factor XII