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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.
AuthorsWilly Jablonka, Michalis Kotsyfakis, Daniella M Mizurini, Robson Q Monteiro, Jan Lukszo, Steven K Drake, José M C Ribeiro, John F Andersen
JournalPloS one (PLoS One) Vol. 10 Issue 8 Pg. e0133991 ( 2015) ISSN: 1932-6203 [Electronic] United States
PMID26244557 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Anticoagulants
  • Peptides
  • Thrombin
Topics
  • Amino Acid Sequence
  • Animals
  • Anticoagulants (chemistry, isolation & purification, pharmacology)
  • Blood Coagulation (drug effects)
  • Blood Coagulation Tests
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Peptides (chemistry, isolation & purification, pharmacology)
  • Platelet Aggregation (drug effects)
  • Sequence Alignment
  • Thrombin (antagonists & inhibitors, metabolism)
  • Thrombosis (drug therapy)
  • Ticks (chemistry)

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