Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs

• Published in: Nature communications Vol. 11; no. 1; pp. 1 - 13
• Main Authors: Wilbs, Jonas, Kong, Xu-Dong, Middendorp, Simon J., Prince, Raja, Cooke, Alida, Demarest, Caitlin T., Abdelhafez, Mai M., Roberts, Kalliope, Umei, Nao, Gonschorek, Patrick, Lamers, Christina, Deyle, Kaycie, Rieben, Robert, Cook, Keith E., Angelillo-Scherrer, Anne, Heinis, Christian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 49/75; 631/154/309/2144; 631/154/51/2313; 64/60; 692/699/75/593/567; 82/83; Anticoagulants; Bleeding; Blood coagulation; Coagulation; Coagulation factor XII; Coagulation factors; Humanities and Social Sciences; Inhibitors; Lungs; multidisciplinary; Oxygenation; Peptide inhibitors; Peptides; Rabbits; Science; Science (multidisciplinary); Stability analysis; Swine; Thromboembolism; Thrombosis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17648-w

Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with sub-nanomolar activity ( K i  = 370 ± 40 pM) and a high stability ( t 1/2  > 5 days in plasma), allowing for the preclinical evaluation of a first synthetic FXIIa inhibitor. This 1899 Da molecule, termed FXII900, efficiently blocks FXIIa in mice, rabbits, and pigs. We found that it reduces ferric-chloride-induced experimental thrombosis in mice and suppresses blood coagulation in an extracorporeal membrane oxygenation (ECMO) setting in rabbits, all without increasing the bleeding risk. This shows that FXIIa activity is controllable in vivo with a synthetic inhibitor, and that the inhibitor FXII900 is a promising candidate for safe thromboprotection in acute medical conditions. Inhibiting thrombosis without inducing bleeding is a major challenge for anticoagulant agents. Here the authors describe a synthetic FXIIa inhibitor able to efficiently prevent thrombosis in mice and suppress coagulation in artificial lungs in rabbits without increasing the risk of bleeding.