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

Jonas Wilbs, Xu-Dong Kong, Simon J. Middendorp, Raja Prince, Alida Cooke, Caitlin T. Demarest, Mai M. Abdelhafez, Kalliope Roberts, Nao Umei, Patrick Gonschorek, Christina Lamers, Kaycie Deyle, Robert Rieben, Keith E. Cook, Anne Angelillo-Scherrer and Christian Heinis ()
Additional contact information
Jonas Wilbs: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Xu-Dong Kong: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Simon J. Middendorp: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Raja Prince: Bern University Hospital, University of Bern
Alida Cooke: Carnegie Mellon University
Caitlin T. Demarest: Carnegie Mellon University
Mai M. Abdelhafez: University of Bern
Kalliope Roberts: Carnegie Mellon University
Nao Umei: Carnegie Mellon University
Patrick Gonschorek: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Christina Lamers: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Kaycie Deyle: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Robert Rieben: University of Bern
Keith E. Cook: Carnegie Mellon University
Anne Angelillo-Scherrer: Bern University Hospital, University of Bern
Christian Heinis: Ecole Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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 (Ki = 370 ± 40 pM) and a high stability (t1/2 > 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.

Date: 2020
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DOI: 10.1038/s41467-020-17648-w

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