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Clinical Pharmacology & Biopharmaceutics | ISSN : 2167-065X
Volume 7
September 18-19, 2018 | Amsterdam, Netherlands
6
th
European Biopharma Congress
Euro Biopharma 2018
Anovel class of parenteral anticoagulant agents for percutaneous coronary intervention (PCI) based on tick thrombin
inhibitors
R Manjunatha Kini
National University of Singapore, Singapore
H
ematophagous insects depend on potent anticoagulant and antiplatelet agents for securing their blood meals. We identified a novel
class of thrombin inhibitors, named as ixothrins, from the salivary gland extracts of ticks. We isolated and characterized variegin and
avathrin from the salivary gland extracts of tropical bont tick
(Amblyomma variegatum)
. They are among the smallest thrombin inhibitors
found in nature. We examined the structure-function relationships of variegin, avathrin and ultravariegin using a number of mutants. We
also determined the X-ray crystal structure of thrombin-variegin and thrombin-avathrin complexes. They interact with exosite I, prime
subsites and active site of thrombin. Based on the structure as well as the prior knowledge on thrombin inhibitors, we designed several
peptides to understand the interaction between thrombin and these inhibitors. These peptides cover a diverse spectrum of potency, kinetics
and mechanism of inhibition, including peptides with affinities ranging from low picomolar to nanomolar values, with fast and slow tight
binding, displaying competitive and non-competitive inhibition. We evaluated the antithrombotic efficacy (carotid artery thrombosis and
stent thrombosis models) and bleeding side effects (tail incision and ear bleeding models) of variegin in rats and pigs, respectively. The
results strongly support the superior antithrombotic efficacy of variegin with minimal bleeding in comparison with comparator drugs,
heparin and hirulog (Bivaluridin or Angiomax
®
). Thus, ixothrins may have the potential in developing parenteral anticoagulant agents for
percutaneous coronary intervention (PCI).
dbskinim@nus.edu.sgClin Pharmacol Biopharm 2018, Volume:7
DOI: 10.4172/2167-065X-C1-029