A Synthetic Factor XIIa Inhibitor Blocks Selectively Intrinsic Coagulation Initiation.

Baeriswyl, Vanessa; Calzavarini, Sara; Chen, Shiyu; Zorzi, Alessandro; Bologna, Luca; Angelillo, Anne; Heinis, Christian (2015). A Synthetic Factor XIIa Inhibitor Blocks Selectively Intrinsic Coagulation Initiation. ACS Chemical Biology, 10(8), pp. 1861-1870. American Chemical Society 10.1021/acschembio.5b00103

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Coagulation factor XII (FXII) inhibitors are of interest for the study of the protease in the intrinsic coagulation pathway, for the suppression of contact activation in blood coagulation assays, and they have potential application in antithrombotic therapy. However, synthetic FXII inhibitors developed to date have weak binding affinity and/or poor selectivity. Herein, we developed a peptide macrocycle that inhibits activated FXII (FXIIa) with an inhibitory constant Ki of 22 nM and a selectivity of >2000-fold over other proteases. Sequence and structure analysis revealed that one of the two macrocyclic rings of the in vitro evolved peptide mimics the combining loop of corn trypsin inhibitor, a natural protein-based inhibitor of FXIIa. The synthetic inhibitor blocked intrinsic coagulation initiation without affecting extrinsic coagulation. Furthermore, the peptide macrocycle efficiently suppressed plasma coagulation triggered by contact of blood with sample tubes and allowed specific investigation of tissue factor initiated coagulation.

Item Type:

Journal Article (Original Article)

Division/Institute:

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:

Calzavarini, Sara; Bologna, Luca and Angelillo, Anne

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1554-8929

Publisher:

American Chemical Society

Language:

English

Submitter:

Verena Zwahlen

Date Deposited:

24 Mar 2016 14:57

Last Modified:

24 Mar 2016 14:57

Publisher DOI:

10.1021/acschembio.5b00103

PubMed ID:

25989088

BORIS DOI:

10.7892/boris.78874

URI:

https://boris.unibe.ch/id/eprint/78874

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