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

Wilbs, Jonas; Kong, Xu-Dong; Middendorp, Simon J; Prince, Raja; Cooke, Alida; Demarest, Caitlin T; Abd El Hafez, Mai Moustafa Ahmed; Roberts, Kalliope; Umei, Nao; Gonschorek, Patrick; Lamers, Christina; Deyle, Kaycie; Rieben, Robert; Cook, Keith E; Angelillo, Anne; Heinis, Christian (2020). Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs. Nature communications, 11(1), p. 3890. Nature Publishing Group 10.1038/s41467-020-17648-w

[img]
Preview
Text
Cyclic.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (1MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Herz und Gefässe
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Handchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Hämatologie (Erwachsene)

UniBE Contributor:

Abd El Hafez, Mai Moustafa Ahmed; Rieben, Robert and Angelillo, Anne

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Pierrette Durand Lüthi

Date Deposited:

11 Aug 2020 14:38

Last Modified:

11 Mar 2021 07:22

Publisher DOI:

10.1038/s41467-020-17648-w

PubMed ID:

32753636

BORIS DOI:

10.7892/boris.145764

URI:

https://boris.unibe.ch/id/eprint/145764

Actions (login required)

Edit item Edit item
Provide Feedback