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Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin.

ABSTRACT: A group of peptides from the salivary gland of the tick Hyalomma marginatum rufipes, a vector of Crimean Congo hemorrhagic fever show weak similarity to the madanins, a group of thrombin-inhibitory peptides from a second tick species, Haemaphysalis longicornis. We have evaluated the anti-serine protease activity of one of these H. marginatum peptides that has been given the name hyalomin-1. Hyalomin-1 was found to be a selective inhibitor of thrombin, blocking coagulation of plasma and inhibiting S2238 hydrolysis in a competitive manner with an inhibition constant (Ki) of 12 nM at an ionic strength of 150 mM. It also blocks the thrombin-mediated activation of coagulation factor XI, thrombin-mediated platelet aggregation, and the activation of coagulation factor V by thrombin. Hyalomin-1 is cleaved at a canonical thrombin cleavage site but the cleaved products do not inhibit coagulation. However, the C-terminal cleavage product showed non-competitive inhibition of S2238 hydrolysis. A peptide combining the N-terminal parts of the molecule with the cleavage region did not interact strongly with thrombin, but a 24-residue fragment containing the cleavage region and the C-terminal fragment inhibited the enzyme in a competitive manner and also inhibited coagulation of plasma. These results suggest that the peptide acts by binding to the active site as well as exosite I or the autolysis loop of thrombin. Injection of 2.5 mg/kg of hyalomin-1 increased arterial occlusion time in a mouse model of thrombosis, suggesting this peptide could be a candidate for clinical use as an antithrombotic.

SUBMITTER: Jablonka W

PROVIDER: S-EPMC4526366 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin.

Jablonka Willy W Kotsyfakis Michalis M Mizurini Daniella M DM Monteiro Robson Q RQ Lukszo Jan J Drake Steven K SK Ribeiro José M C JM Andersen John F JF

PloS one 20150805 8

A group of peptides from the salivary gland of the tick Hyalomma marginatum rufipes, a vector of Crimean Congo hemorrhagic fever show weak similarity to the madanins, a group of thrombin-inhibitory peptides from a second tick species, Haemaphysalis longicornis. We have evaluated the anti-serine protease activity of one of these H. marginatum peptides that has been given the name hyalomin-1. Hyalomin-1 was found to be a selective inhibitor of thrombin, blocking coagulation of plasma and inhibitin ...[more]

PMID: 26244557

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Project description:Ticks are arthropod vectors of pathogens of both Veterinary and Public health importance. Acaricide application, which is currently the mainstay of tick control, is hampered by high cost, the need for regular application and a selection of multi-acaricide resistant tick populations. In light of this, future tick control approaches are poised to rely on the integration of rational acaricide application and other methods, such as vaccination. To contribute to systematic research-guided efforts to produce anti-tick vaccines, we carried out an in-silico analysis of tick aquaporin-1 (AQP1) protein in order to identify tick-specific AQP1 peptide motifs that can be used in future peptide anti-tick vaccine development. We carried out multiple sequence alignment (MSA), motif analysis, homology modeling, and structural analysis to identify tick-specific AQP1 peptide motifs. BepiPred, Chou and Fasman-Turn, Karplus and Schulz Flexibility, and Parker-Hydrophilicity prediction models were used to predict these motifs' potential to induce B cell mediated immune responses. The tick AQP1 (GenBankID: QDO67142.1) protein was largely similar to the bovine AQP1 (PDB:1J4N) (23 % sequence similarity; Structural superimposition of the homology model and 14JN homotetramers gave an RMSD = 3.269 while superimposition of a single chain gave an RMSD = 1.475). Tick and bovine AQP1 transmembrane domains were largely similar while their extracellular and cytoplasmic domain loops showed variation. Two tick-specific AQP1 peptide motifs; M7 (residues 106-125, p = 5.4e-25), and M8 (residues 85-104, p = 3.3e-24) were identified. These two motifs are located on the extra-cellular AQP1 domain. Motifs; M7 and M8 showed the highest Parker-Hydrophilicity prediction immunogenicity scores of 1.784 and 1.536, respectively. These two motifs can be a good starting point for the development of potential tick AQP1 peptide-based anti-tick vaccines. Further analyses such as molecular dynamics, in vitro assays, and in vivo immunization assays are required to validate these findings.

Dataset Information

Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin.

Publications

Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin.

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