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Thromb Haemost 2018; 118(10): 1713-1728
DOI: 10.1055/s-0038-1669785
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

The First Intrinsic Tenase Complex Inhibitor with Serine Protease Structure Offers a New Perspective in Anticoagulant Therapy

Zorica Latinović
1   Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
2   Jožef Stefan International Postgraduate School, Ljubljana, Slovenia
,
Adrijana Leonardi
1   Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
,
Lidija Kovačič
1   Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
3   Global Drug Development, Novartis Ireland Ltd, Dublin, Ireland
,
Cho Yeow Koh
4   Protein Science Laboratory, Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore
5   Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
,
Jernej Šribar
1   Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
,
Alenka Trampuš Bakija
6   Division of Pediatrics, University Medical Center Ljubljana, University of Ljubljana, Ljubljana, Slovenia
,
Divi Venkateswarlu
7   Department of Chemistry, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, United States
,
R. Manjunatha Kini
4   Protein Science Laboratory, Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore
,
Igor Križaj
1   Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
› Author Affiliations
Funding This work was supported by a grant from the Slovenian Research Agency (P1–0207), by the FP7 WeNMR (No. 261572) and H2020 West-Life (No. 675858) grants, and by a grant for the Research Cooperation of Doctoral Students Abroad in Year 2014 (Official Gazette of the Republic of Slovenia, No. 89/14).
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Publication History

17 May 2018

24 July 2018

Publication Date:
20 September 2018 (online)

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Abstract

Components of the intrinsic blood coagulation pathway, among them factor VIIIa (FVIIIa), have been recognized as suitable therapeutic targets to treat venous thromboembolism, pathological process behind two very serious cardiovascular diseases, deep vein thrombosis and pulmonary embolism. Here, we describe a unique glycoprotein from the nose-horned viper (Vipera ammodytes ammodytes [Vaa]) venom, Vaa serine proteinase homolog 1 (VaaSPH-1), structurally a serine protease but without an enzymatic activity and expressing potent anticoagulant action in human blood. We demonstrated that one of its targets in the blood coagulation system is FVIIIa of the intrinsic tenase complex, where it antagonizes the binding of FIXa. Anticoagulants with such characteristics are intensively sought, as they would be much safer for medical application as the contemporary drugs, which frequently induce excessive bleeding and other complications. VaaSPH-1 is unlikely to be orally available for chronic usage as it has molecular mass of 35 kDa. However, it represents a very promising template to design low molecular mass FVIIIa-directed anticoagulant substances, based on structural features of the interaction surface between VaaSPH-1 and FVIIIa. To this end, we constructed a three-dimensional model of VaaSPH-1 bound to FVIIIa. The model exposes the 157–loop and the preceding α-helix as the most appropriate structural elements of VaaSPH-1 to be considered as a guideline to synthesize small FVIIIa-binding molecules, potential new generation of anticoagulants.

Keywords

snake venoms - haemostasis - coagulation inhibitors - factor VIII inhibitors - venous thrombosis

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