Recent advances in the discovery and development of factor XI/XIa inhibitors
- 4 May 2018
- journal article
- review article
- Published by Wiley in Medicinal Research Reviews
- Vol. 38 (6), 1974-2023
- https://doi.org/10.1002/med.21503
Abstract
Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa, which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI (FXI)/FXIa system have emerged as a paradigm‐shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life‐threatening risk of internal bleeding. Several inhibitors of FXI/FXIa proteins have been discovered or designed over the last decade including polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, antibodies, and aptamers. Antisense oligonucleotides (ASOs), which ultimately reduce the hepatic biosynthesis of FXI, have also been introduced. A phase II study, which included patients undergoing elective primary unilateral total knee arthroplasty, revealed that a specific FXI ASO effectively protects patients against venous thrombosis with a relatively limited risk of bleeding. Initial findings have also demonstrated the potential of FXI/FXIa inhibitors in sepsis, listeriosis, and arterial hypertension. This review highlights various chemical, biochemical, and pharmacological aspects of FXI/FXIa inhibitors with the goal of advancing their development toward clinical use.Keywords
Funding Information
- Research Centers in Minority Institutions (RCMI) Program from the National Institute on Minority Health and Health Disparities of the National Institutes of Health (5G12MD007595)
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (3 P20 GM103424-15S1 5, P20 GM103424-15)
This publication has 173 references indexed in Scilit:
- Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in MiceTranslational Stroke Research, 2012
- Sulfated, low molecular weight lignins inhibit a select group of heparin-binding serine proteasesBiochemical and Biophysical Research Communications, 2012
- Factor XI-Deficient Mice Display Reduced Inflammation, Coagulopathy, and Bacterial Growth during ListeriosisInfection and Immunity, 2012
- Engineering Kunitz Domain 1 (KD1) of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit FibrinolysisPublished by Elsevier BV ,2011
- Emerging principles in protease-based drug discoveryNature Reviews Drug Discovery, 2010
- Coagulation procofactor activation by factor XIaJournal of Thrombosis and Haemostasis, 2010
- Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasisThe Journal of Experimental Medicine, 2009
- Structural and functional features of factor XIJournal of Thrombosis and Haemostasis, 2009
- Characterization of a Heparin-Binding Site on the Catalytic Domain of Factor XIa: Mechanism of Heparin Acceleration of Factor XIa Inhibition by the Serpins Antithrombin and C1-InhibitorBiochemistry, 2009
- Engineering the substrate and inhibitor specificities of human coagulation Factor VIIaBiochemical Journal, 2007