Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma

Joakim E. Swedberg, Guojie Wu, Tunjung Mahatmanto, Thomas Durek, Thomas T. Caradoc-Davies, James C. Whisstock, Ruby H. P. Law, David J. Craik

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Antifibrinolytic drugs provide important pharmacological interventions to reduce morbidity and mortality from excessive bleeding during surgery and after trauma. Current drugs used for inhibiting the dissolution of fibrin, the main structural component of blood clots, are associated with adverse events due to lack of potency, high doses, and nonselective inhibition mechanisms. These drawbacks warrant the development of a new generation of highly potent and selective fibrinolysis inhibitors. Here, we use the 14-amino acid backbone-cyclic sunflower trypsin inhibitor-1 scaffold to design a highly potent (K i = 0.05 nM) inhibitor of the primary serine protease in fibrinolysis, plasmin. This compound displays a million-fold selectivity over other serine proteases in blood, inhibits fibrinolysis in plasma more effectively than the gold-standard therapeutic inhibitor aprotinin, and is a promising candidate for development of highly specific fibrinolysis inhibitors with reduced side effects.

Original languageEnglish
Pages (from-to)552-560
Number of pages9
JournalJournal of Medicinal Chemistry
Volume62
Issue number2
DOIs
Publication statusPublished - 2019

Cite this

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title = "Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma",
abstract = "Antifibrinolytic drugs provide important pharmacological interventions to reduce morbidity and mortality from excessive bleeding during surgery and after trauma. Current drugs used for inhibiting the dissolution of fibrin, the main structural component of blood clots, are associated with adverse events due to lack of potency, high doses, and nonselective inhibition mechanisms. These drawbacks warrant the development of a new generation of highly potent and selective fibrinolysis inhibitors. Here, we use the 14-amino acid backbone-cyclic sunflower trypsin inhibitor-1 scaffold to design a highly potent (K i = 0.05 nM) inhibitor of the primary serine protease in fibrinolysis, plasmin. This compound displays a million-fold selectivity over other serine proteases in blood, inhibits fibrinolysis in plasma more effectively than the gold-standard therapeutic inhibitor aprotinin, and is a promising candidate for development of highly specific fibrinolysis inhibitors with reduced side effects.",
author = "Swedberg, {Joakim E.} and Guojie Wu and Tunjung Mahatmanto and Thomas Durek and Caradoc-Davies, {Thomas T.} and Whisstock, {James C.} and Law, {Ruby H. P.} and Craik, {David J.}",
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doi = "10.1021/acs.jmedchem.8b01139",
language = "English",
volume = "62",
pages = "552--560",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
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Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma. / Swedberg, Joakim E.; Wu, Guojie; Mahatmanto, Tunjung; Durek, Thomas; Caradoc-Davies, Thomas T.; Whisstock, James C.; Law, Ruby H. P.; Craik, David J.

In: Journal of Medicinal Chemistry, Vol. 62, No. 2, 2019, p. 552-560.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma

AU - Swedberg, Joakim E.

AU - Wu, Guojie

AU - Mahatmanto, Tunjung

AU - Durek, Thomas

AU - Caradoc-Davies, Thomas T.

AU - Whisstock, James C.

AU - Law, Ruby H. P.

AU - Craik, David J.

PY - 2019

Y1 - 2019

N2 - Antifibrinolytic drugs provide important pharmacological interventions to reduce morbidity and mortality from excessive bleeding during surgery and after trauma. Current drugs used for inhibiting the dissolution of fibrin, the main structural component of blood clots, are associated with adverse events due to lack of potency, high doses, and nonselective inhibition mechanisms. These drawbacks warrant the development of a new generation of highly potent and selective fibrinolysis inhibitors. Here, we use the 14-amino acid backbone-cyclic sunflower trypsin inhibitor-1 scaffold to design a highly potent (K i = 0.05 nM) inhibitor of the primary serine protease in fibrinolysis, plasmin. This compound displays a million-fold selectivity over other serine proteases in blood, inhibits fibrinolysis in plasma more effectively than the gold-standard therapeutic inhibitor aprotinin, and is a promising candidate for development of highly specific fibrinolysis inhibitors with reduced side effects.

AB - Antifibrinolytic drugs provide important pharmacological interventions to reduce morbidity and mortality from excessive bleeding during surgery and after trauma. Current drugs used for inhibiting the dissolution of fibrin, the main structural component of blood clots, are associated with adverse events due to lack of potency, high doses, and nonselective inhibition mechanisms. These drawbacks warrant the development of a new generation of highly potent and selective fibrinolysis inhibitors. Here, we use the 14-amino acid backbone-cyclic sunflower trypsin inhibitor-1 scaffold to design a highly potent (K i = 0.05 nM) inhibitor of the primary serine protease in fibrinolysis, plasmin. This compound displays a million-fold selectivity over other serine proteases in blood, inhibits fibrinolysis in plasma more effectively than the gold-standard therapeutic inhibitor aprotinin, and is a promising candidate for development of highly specific fibrinolysis inhibitors with reduced side effects.

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U2 - 10.1021/acs.jmedchem.8b01139

DO - 10.1021/acs.jmedchem.8b01139

M3 - Article

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SP - 552

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JF - Journal of Medicinal Chemistry

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