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

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 (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 (ECM

SUBMITTER: Wilbs J 

PROVIDER: S-EPMC7403315 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature