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Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia

The inhibition of factor XIa (FXIa) is a trending paradigm for the development of new generations of anticoagulants without a substantial risk of bleeding. In this report, we present the discovery of a benzyl tetra‐phosphonate derivative as a potent and selective inhibitor of human FXIa. Biochemical...

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Autores principales: Kar, Srabani, Mottamal, Madhusoodanan, Al‐Horani, Rami A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654249/
https://www.ncbi.nlm.nih.gov/pubmed/33204588
http://dx.doi.org/10.1002/open.202000277
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author Kar, Srabani
Mottamal, Madhusoodanan
Al‐Horani, Rami A.
author_facet Kar, Srabani
Mottamal, Madhusoodanan
Al‐Horani, Rami A.
author_sort Kar, Srabani
collection PubMed
description The inhibition of factor XIa (FXIa) is a trending paradigm for the development of new generations of anticoagulants without a substantial risk of bleeding. In this report, we present the discovery of a benzyl tetra‐phosphonate derivative as a potent and selective inhibitor of human FXIa. Biochemical screening of four phosphonate/phosphate derivatives has led to the identification of the molecule that inhibited human FXIa with an IC(50) value of ∼7.4 μM and a submaximal efficacy of ∼68 %. The inhibitor was at least 14‐fold more selective to FXIa over thrombin, factor IXa, factor Xa, and factor XIIIa. It also inhibited FXIa‐mediated activation of factor IX and prolonged the activated partial thromboplastin time of human plasma. In Michaelis‐Menten kinetics experiment, inhibitor 1 reduced the V(MAX) of FXIa hydrolysis of a chromogenic substrate without significantly affecting its K(M) suggesting an allosteric mechanism of inhibition. The inhibitor also disrupted the formation of FXIa – antithrombin complex and inhibited thrombin‐mediated and factor XIIa‐mediated formation of FXIa from its zymogen factor XI. Inhibitor 1 has been proposed to bind to or near the heparin/polyphosphate‐binding site in the catalytic domain of FXIa. Overall, inhibitor 1 is the first benzyl tetraphosphonate small molecule that allosterically inhibits human FXIa, blocks its physiological function, and prevents its zymogen activation by other clotting factors under in vitro conditions. Thus, we put forward benzyl tetra‐phosphonate 1 as a novel lead inhibitor of human FXIa to guide future efforts in the development of allosteric anticoagulants.
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spelling pubmed-76542492020-11-16 Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia Kar, Srabani Mottamal, Madhusoodanan Al‐Horani, Rami A. ChemistryOpen Full Papers The inhibition of factor XIa (FXIa) is a trending paradigm for the development of new generations of anticoagulants without a substantial risk of bleeding. In this report, we present the discovery of a benzyl tetra‐phosphonate derivative as a potent and selective inhibitor of human FXIa. Biochemical screening of four phosphonate/phosphate derivatives has led to the identification of the molecule that inhibited human FXIa with an IC(50) value of ∼7.4 μM and a submaximal efficacy of ∼68 %. The inhibitor was at least 14‐fold more selective to FXIa over thrombin, factor IXa, factor Xa, and factor XIIIa. It also inhibited FXIa‐mediated activation of factor IX and prolonged the activated partial thromboplastin time of human plasma. In Michaelis‐Menten kinetics experiment, inhibitor 1 reduced the V(MAX) of FXIa hydrolysis of a chromogenic substrate without significantly affecting its K(M) suggesting an allosteric mechanism of inhibition. The inhibitor also disrupted the formation of FXIa – antithrombin complex and inhibited thrombin‐mediated and factor XIIa‐mediated formation of FXIa from its zymogen factor XI. Inhibitor 1 has been proposed to bind to or near the heparin/polyphosphate‐binding site in the catalytic domain of FXIa. Overall, inhibitor 1 is the first benzyl tetraphosphonate small molecule that allosterically inhibits human FXIa, blocks its physiological function, and prevents its zymogen activation by other clotting factors under in vitro conditions. Thus, we put forward benzyl tetra‐phosphonate 1 as a novel lead inhibitor of human FXIa to guide future efforts in the development of allosteric anticoagulants. John Wiley and Sons Inc. 2020-11-10 /pmc/articles/PMC7654249/ /pubmed/33204588 http://dx.doi.org/10.1002/open.202000277 Text en © 2020 The Authors. Published by Wiley-VCH GmbH This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Full Papers
Kar, Srabani
Mottamal, Madhusoodanan
Al‐Horani, Rami A.
Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia
title Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia
title_full Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia
title_fullStr Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia
title_full_unstemmed Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia
title_short Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia
title_sort discovery of benzyl tetraphosphonate derivative as inhibitor of human factor xia
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654249/
https://www.ncbi.nlm.nih.gov/pubmed/33204588
http://dx.doi.org/10.1002/open.202000277
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