Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32753636.
- Also identified by DOI 10.1038/s41467-020-17648-w and PMC identifier 7403315.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>i</sub> = 370 ± 40 pM) and a high stability (t<sub>1/2</sub> > 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.
Medical subject headings
- Anticoagulants
- Blood Coagulation
- Factor XIIa
- Peptides, Cyclic
- Thrombosis