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Projects / Programmes source: ARIS

Development of an innovative drug to treat venous thromboembolism based on a unique viper venom anticoagulant

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Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
snake venom, haemostasis, anticoagulat, intrinsic tenase, factor VIIIa, inhibitor, venous thrombosis, drug
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Points
4,216.74
A''
355.92
A'
1,964.67
A1/2
2,560.49
CI10
5,003
CImax
211
h10
31
A1
14.5
A3
0.71
Data for the last 5 years (citations for the last 10 years) on April 24, 2024; A3 for period 2018-2022
Data for ARIS tenders ( 04.04.2019 – Programme tender, archive )
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Database Linked records Citations Pure citations Average pure citations
WoS  477  9,737  7,443  15.6 
Scopus  473  10,611  8,242  17.42 
Researchers (21)
no. Code Name and surname Research area Role Period No. of publications
1.  15595  Katarina Babnik    Technical associate  2020 - 2024  8 
2.  15637  PhD Mojca Božič Mijovski  Cardiovascular system  Researcher  2020 - 2024  211 
3.  18122  Boštjan Drolc  Veterinarian medicine  Technical associate  2020 - 2024  10 
4.  12449  PhD Robert Frangež  Veterinarian medicine  Researcher  2020 - 2024  280 
5.  50498  PhD Adrijan Ivanušec  Biochemistry and molecular biology  Researcher  2022 - 2024  27 
6.  55063  Špela Koren  Biochemistry and molecular biology  Junior researcher  2021 - 2024  21 
7.  00412  PhD Igor Križaj  Biochemistry and molecular biology  Head  2020 - 2024  726 
8.  52369  Ana Kump  Biochemistry and molecular biology  Researcher  2021  40 
9.  18802  PhD Adrijana Leonardi  Biochemistry and molecular biology  Researcher  2020 - 2024  156 
10.  39242  PhD Nina Mikec  Biochemistry and molecular biology  Researcher  2023 - 2024  20 
11.  56248  Leja Perne  Biochemistry and molecular biology  Technical associate  2022 - 2024  11 
12.  20213  PhD Toni Petan  Biochemistry and molecular biology  Researcher  2020 - 2024  177 
13.  55106  Aljaž Pirnat  Cardiovascular system  Researcher  2022 - 2024  0 
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  108 
17.  39693  Anja Švigelj  Oncology  Researcher  2020 - 2024  6 
18.  20128  PhD Alenka Trampuš Bakija  Cardiovascular system  Researcher  2020 - 2024  128 
19.  13334  PhD Milka Vrecl Fazarinc  Veterinarian medicine  Researcher  2020 - 2024  269 
20.  56000  Mia Žganjar  Biochemistry and molecular biology  Researcher  2022 - 2024  11 
21.  22588  PhD Monika Cecilija Žužek  Veterinarian medicine  Researcher  2020 - 2024  67 
Organisations (3)
no. Code Research organisation City Registration number No. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,724 
2.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  77,465 
3.  0406  University of Ljubljana, Veterinary Faculty  Ljubljana  1627139  10,777 
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.
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