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

Nat Commun. 2020 Aug 4;11(1):3890. 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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / pharmacology*
  • Blood Coagulation / drug effects*
  • Chlorides / adverse effects
  • Cloning, Molecular
  • Disease Models, Animal
  • Drug Discovery
  • Extracorporeal Membrane Oxygenation / methods
  • Factor XII / antagonists & inhibitors
  • Factor XIIa / antagonists & inhibitors*
  • Female
  • Ferric Compounds / adverse effects
  • Humans
  • Lung
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptides, Cyclic / drug effects*
  • Rabbits
  • Recombinant Proteins / pharmacology
  • Swine
  • Thrombosis / prevention & control*


  • Anticoagulants
  • Chlorides
  • Ferric Compounds
  • Peptides, Cyclic
  • Recombinant Proteins
  • Factor XII
  • Factor XIIa
  • ferric chloride