Projects / Programmes
Development of an innovative drug to treat venous thromboembolism based on a unique viper venom anticoagulant
Code |
Science |
Field |
Subfield |
1.05.00 |
Natural sciences and mathematics |
Biochemistry and molecular biology |
|
Code |
Science |
Field |
1.06 |
Natural Sciences |
Biological sciences |
snake venom, haemostasis, anticoagulat, intrinsic tenase, factor VIIIa, inhibitor, venous thrombosis, drug
Researchers (21)
no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
1. |
15595 |
Katarina Babnik |
|
Technical associate |
2020 - 2024 |
8 |
2. |
15637 |
PhD Mojca Božič Mijovski |
Cardiovascular system |
Researcher |
2020 - 2024 |
223 |
3. |
18122 |
Boštjan Drolc |
Veterinarian medicine |
Technical associate |
2020 - 2024 |
10 |
4. |
12449 |
PhD Robert Frangež |
Veterinarian medicine |
Researcher |
2020 - 2024 |
289 |
5. |
50498 |
PhD Adrijan Ivanušec |
Biochemistry and molecular biology |
Researcher |
2022 - 2024 |
28 |
6. |
55063 |
Špela Koren |
Biochemistry and molecular biology |
Junior researcher |
2021 - 2024 |
23 |
7. |
00412 |
PhD Igor Križaj |
Biochemistry and molecular biology |
Head |
2020 - 2024 |
740 |
8. |
52369 |
Ana Kump |
Biochemistry and molecular biology |
Researcher |
2021 |
43 |
9. |
18802 |
PhD Adrijana Leonardi |
Biochemistry and molecular biology |
Researcher |
2020 - 2024 |
162 |
10. |
39242 |
PhD Nina Mikec |
Biochemistry and molecular biology |
Researcher |
2023 - 2024 |
22 |
11. |
56248 |
Leja Perne |
Biochemistry and molecular biology |
Technical associate |
2022 - 2024 |
13 |
12. |
20213 |
PhD Toni Petan |
Biochemistry and molecular biology |
Researcher |
2020 - 2024 |
182 |
13. |
55106 |
Aljaž Pirnat |
Cardiovascular system |
Researcher |
2022 - 2024 |
3 |
14. |
04570 |
PhD Jože Pungerčar |
Biochemistry and molecular biology |
Researcher |
2020 - 2024 |
320 |
15. |
18125 |
Jasna Šporar |
|
Technical associate |
2020 - 2024 |
0 |
16. |
21553 |
PhD Jernej Šribar |
Biochemistry and molecular biology |
Researcher |
2020 - 2024 |
114 |
17. |
39693 |
Anja Švigelj |
Oncology |
Researcher |
2020 - 2024 |
6 |
18. |
20128 |
PhD Alenka Trampuš Bakija |
Cardiovascular system |
Researcher |
2020 - 2024 |
130 |
19. |
13334 |
PhD Milka Vrecl Fazarinc |
Veterinarian medicine |
Researcher |
2020 - 2024 |
273 |
20. |
56000 |
Mia Žganjar |
Biochemistry and molecular biology |
Researcher |
2022 - 2024 |
13 |
21. |
22588 |
PhD Monika Cecilija Žužek |
Veterinarian medicine |
Researcher |
2020 - 2024 |
74 |
Organisations (3)
Abstract
Components of the intrinsic blood coagulation pathway, among them factor VIIIa (FVIIIa), have been recognized as the most suitable therapeutic targets to treat venous thromboembolism (VTE), pathological process behind two very serious cardiovascular diseases (CVD), deep vein thrombosis and pulmonary embolism. Although VTE is the third leading cause of the CVD-related mortality, an adequate therapy is still not available. There is an enormous need for new anticoagulants to cure VTE, which would not impose high risk of bleeding on patients. Recently, we described a glycoprotein from the nose-horned viper (Vipera ammodytes ammodytes; Vaa) venom, VaaSPH-1, structurally a serine protease but without an enzymatic activity, which expresses a potent anticoagulant action in human blood. We demonstrated that its major target in the blood coagulation system is FVIIIa. VaaSPH-1 antagonizes the binding of FIXa to FVIIIa so the intrinsic tenase complex is not formed. Anticoagulants with such characteristics are intensively sought as they would be much safer for medical application than contemporary drugs. The latter namely target coagulation factors that are essential for hemostasis, so they frequently induce life-threatening bleeding complications. VaaSPH-1 is unlikely to be orally available for chronic usage due to its high molecular mass, however, it represents a very promising template to design low molecular mass (LMM) FVIIIa-directed anticoagulant substances, based on unique structural features of the interaction surface between VaaSPH-1 and FVIIIa. That this snake venom molecule is indeed a very promising template to design a novel type of selective intrinsic tenase inhibitors to attenuate thrombus formation safely and effectively was confirmed by immediate highlighting of our results in the expert community. The overarching objective of this project is thus to address the venous thrombosis therapy deficit by extending the studies of VaaSPH-1 towards development of original VaaSPH-1-based substances to attenuate thrombus formation and propagation without increasing the risk of bleeding. The research consortium of 3 domestic (Jožef Stefan Institute Ljubljana, Veterinary faculty of the University of Ljubljana, Medical Centre Ljubljana) and 3 foreign (National University of Singapore, Novartis Basel, North Carolina State University) expert groups, experienced, highly competent and properly equipped, with already established efficient collaboration on this topic (Latinović et al., 2018), is eager to continue their work. Regarding currently inadequate treatment of VTE, a high relevance of such endeavour is unquestionable. To this end, our priorities are: (1) to develop a procedure for production of recombinant VaaSPH-1 and its mutants for detail characterization of interactions of this molecule with FVIIIa but also with other components of the haemostatic system, (2) to experimentally verify, using interaction site mapping and VaaSPH-1 mutants, the in silico constructed 3D model of the VaaSPH-1–FVIIIa complex and to define crucial structural elements of the interaction between these two proteins, (3) to design and synthesize LMM molecules based on the VaaSPH-1 structure contacting FVIIIa, (4) to develop a surface plasmon resonance-based high-throughput assay to measure the affinity of LMM molecules for FVIII(a), (5) to evaluate the effects of LMM anticoagulant candidates on blood coagulation and intrinsic tenase activity, and, in the iterative structure-activity optimization procedure, to create an optimal LMM lead compound (6) to be finally tested in the mouse model for its in vivo anticoagulant potential. We plan to end up the project with an innovative VaaSPH-1-based LMM FIXa antagonist ready to enter preclinical studies. Expectedly of a very high impact, we will define in this way a new line of selective inhibitors of the intrinsic blood coagulation pathway with a very high prospect of development towards safe medicine to treat VTE.