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Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Modrzycka, Sylwia 
Kołt, Sonia 
Adams, Ty E 
Potoczek, Stanisław 
Huntington, James A 

Abstract

Anticoagulation therapy is a mainstay of the treatment of thrombotic disorders; however, conventional anticoagulants trade antithrombotic benefits for bleeding risk. Factor (f) XI deficiency, known as hemophilia C, rarely causes spontaneous bleeding, suggesting that fXI plays a limited role in hemostasis. In contrast, individuals with congenital fXI deficiency display a reduced incidence of ischemic stroke and venous thromboembolism, indicating that fXI plays a role in thrombosis. For these reasons, there is intense interest in pursuing fXI/factor XIa (fXIa) as targets for achieving antithrombotic benefit with reduced bleeding risk. To obtain selective inhibitors of fXIa, we employed libraries of natural and unnatural amino acids to profile fXIa substrate preferences. We developed chemical tools for investigating fXIa activity, such as substrates, inhibitors, and activity-based probes (ABPs). Finally, we demonstrated that our ABP selectively labels fXIa in the human plasma, making this tool suitable for further studies on the role of fXIa in biological samples.

Description

Funder: European Regional Development Fund

Keywords

Humans, Factor XIa, Fibrinolytic Agents, Hemostasis, Anticoagulants, Thrombosis, Factor XI

Journal Title

J Med Chem

Conference Name

Journal ISSN

0022-2623
1520-4804

Volume Title

66

Publisher

American Chemical Society (ACS)
Sponsorship
Fundacja na rzecz Nauki Polskiej (TEAM/2017-4/32)