Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin

Abstract Thrombin is a multifunctional enzyme with a key role in the coagulation cascade. Its functional modulation can culminate into normal blood coagulation or thrombosis. Thus, the identification of novel potent inhibitors of thrombin are of immense importance. Sculptin is the first specific thr...

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Autores principales:	Asif Iqbal, Mauricio Barbugiani Goldfeder, Rafael Marques-Porto, Huma Asif, Jean Gabriel de Souza, Fernanda Faria, Ana Marisa Chudzinski-Tavassi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ba1295f0327f41e988619873c275f432
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spelling	oai:doaj.org-article:ba1295f0327f41e988619873c275f4322021-12-02T11:41:01ZRevisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin10.1038/s41598-017-01486-w2045-2322https://doaj.org/article/ba1295f0327f41e988619873c275f4322017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01486-whttps://doaj.org/toc/2045-2322Abstract Thrombin is a multifunctional enzyme with a key role in the coagulation cascade. Its functional modulation can culminate into normal blood coagulation or thrombosis. Thus, the identification of novel potent inhibitors of thrombin are of immense importance. Sculptin is the first specific thrombin inhibitor identified in the transcriptomics analysis of tick’s salivary glands. It consists of 168 residues having four similar repeats and evolutionary diverged from hirudin. Sculptin is a competitive, specific and reversible inhibitor of thrombin with a Ki of 18.3 ± 1.9 pM (k on 4.04 ± 0.03 × 107 M−1 s−1 and k off 0.65 ± 0.04 × 10−3 s−1). It is slowly consumed by thrombin eventually losing its activity. Contrary, sculptin is hydrolyzed by factor Xa and each polypeptide fragment is able to inhibit thrombin independently. A single domain of sculptin alone retains ~45% of inhibitory activity, which could bind thrombin in a bivalent fashion. The formation of a small turn/helical-like structure by active site binding residues of sculptin might have made it a more potent thrombin inhibitor. In addition, sculptin prolongs global coagulation parameters. In conclusion, sculptin and its independent domain(s) have strong potential to become novel antithrombotic therapeutics.Asif IqbalMauricio Barbugiani GoldfederRafael Marques-PortoHuma AsifJean Gabriel de SouzaFernanda FariaAna Marisa Chudzinski-TavassiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Asif Iqbal Mauricio Barbugiani Goldfeder Rafael Marques-Porto Huma Asif Jean Gabriel de Souza Fernanda Faria Ana Marisa Chudzinski-Tavassi Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
description	Abstract Thrombin is a multifunctional enzyme with a key role in the coagulation cascade. Its functional modulation can culminate into normal blood coagulation or thrombosis. Thus, the identification of novel potent inhibitors of thrombin are of immense importance. Sculptin is the first specific thrombin inhibitor identified in the transcriptomics analysis of tick’s salivary glands. It consists of 168 residues having four similar repeats and evolutionary diverged from hirudin. Sculptin is a competitive, specific and reversible inhibitor of thrombin with a Ki of 18.3 ± 1.9 pM (k on 4.04 ± 0.03 × 107 M−1 s−1 and k off 0.65 ± 0.04 × 10−3 s−1). It is slowly consumed by thrombin eventually losing its activity. Contrary, sculptin is hydrolyzed by factor Xa and each polypeptide fragment is able to inhibit thrombin independently. A single domain of sculptin alone retains ~45% of inhibitory activity, which could bind thrombin in a bivalent fashion. The formation of a small turn/helical-like structure by active site binding residues of sculptin might have made it a more potent thrombin inhibitor. In addition, sculptin prolongs global coagulation parameters. In conclusion, sculptin and its independent domain(s) have strong potential to become novel antithrombotic therapeutics.
format	article
author	Asif Iqbal Mauricio Barbugiani Goldfeder Rafael Marques-Porto Huma Asif Jean Gabriel de Souza Fernanda Faria Ana Marisa Chudzinski-Tavassi
author_facet	Asif Iqbal Mauricio Barbugiani Goldfeder Rafael Marques-Porto Huma Asif Jean Gabriel de Souza Fernanda Faria Ana Marisa Chudzinski-Tavassi
author_sort	Asif Iqbal
title	Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
title_short	Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
title_full	Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
title_fullStr	Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
title_full_unstemmed	Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
title_sort	revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ba1295f0327f41e988619873c275f432
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Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin

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