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

[Image: see text] 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 lim...

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Autores principales: Modrzycka, Sylwia, Kołt, Sonia, Adams, Ty E., Potoczek, Stanisław, Huntington, James A., Kasperkiewicz, Paulina, Drąg, Marcin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10041521/
https://www.ncbi.nlm.nih.gov/pubmed/36898159
http://dx.doi.org/10.1021/acs.jmedchem.2c00845
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author Modrzycka, Sylwia
Kołt, Sonia
Adams, Ty E.
Potoczek, Stanisław
Huntington, James A.
Kasperkiewicz, Paulina
Drąg, Marcin
author_facet Modrzycka, Sylwia
Kołt, Sonia
Adams, Ty E.
Potoczek, Stanisław
Huntington, James A.
Kasperkiewicz, Paulina
Drąg, Marcin
author_sort Modrzycka, Sylwia
collection PubMed
description [Image: see text] 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.
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spelling pubmed-100415212023-03-28 Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma Modrzycka, Sylwia Kołt, Sonia Adams, Ty E. Potoczek, Stanisław Huntington, James A. Kasperkiewicz, Paulina Drąg, Marcin J Med Chem [Image: see text] 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. American Chemical Society 2023-03-10 /pmc/articles/PMC10041521/ /pubmed/36898159 http://dx.doi.org/10.1021/acs.jmedchem.2c00845 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Modrzycka, Sylwia
Kołt, Sonia
Adams, Ty E.
Potoczek, Stanisław
Huntington, James A.
Kasperkiewicz, Paulina
Drąg, Marcin
Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma
title Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma
title_full Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma
title_fullStr Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma
title_full_unstemmed Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma
title_short Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma
title_sort fluorescent activity-based probe to image and inhibit factor xia activity in human plasma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10041521/
https://www.ncbi.nlm.nih.gov/pubmed/36898159
http://dx.doi.org/10.1021/acs.jmedchem.2c00845
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