Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs.
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BORIS DOI
Date of Publication
August 4, 2020
Publication Type
Article
Division/Institute
Contributor
Wilbs, Jonas | |
Kong, Xu-Dong | |
Middendorp, Simon J | |
Prince, Raja | |
Cooke, Alida | |
Demarest, Caitlin T | |
Roberts, Kalliope | |
Umei, Nao | |
Gonschorek, Patrick | |
Lamers, Christina | |
Deyle, Kaycie | |
Cook, Keith E | |
Heinis, Christian |
Subject(s)
Series
Nature communications
ISSN or ISBN (if monograph)
2041-1723
Publisher
Nature Publishing Group
Language
English
Publisher DOI
PubMed ID
32753636
Description
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.
File(s)
File | File Type | Format | Size | License | Publisher/Copright statement | Content | |
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Cyclic.pdf | Adobe PDF | 1.75 MB | published |