Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors

Cho Yeow Koh, Norrapat Shih, Christina Y.C. Yip, Aaron Wei Liang Li, Weiming Chen, Fathiah S. Amran, Esther Jia En Leong, Janaki Krishnamoorthy Iyer, Grace Croft, Muhammad Ibrahim Bin Mazlan, Yen Lin Chee, Eng Soo Yap, Dougald M. Monroe, Maureane Hoffman, Richard C. Becker, Dominique P.V. de Kleijn, Vaishali Verma, Amita Gupta, Vijay K. Chaudhary, A. Mark RichardsR. Manjunatha Kini, Mark Y. Chan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.

Original languageEnglish
Article number6912
Pages (from-to)1-16
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 25 Nov 2021

Keywords

  • Amblyomma
  • Animals
  • Antibodies
  • Anticoagulants
  • Antidotes
  • Antithrombins/pharmacology
  • Aspirin
  • Drug Development
  • Drug Discovery
  • Female
  • Fibrinolytic Agents/pharmacology
  • Gene Library
  • Heparin
  • Hirudins
  • Humans
  • Male
  • Peptide Fragments
  • Percutaneous Coronary Intervention/methods
  • Proteomics
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins
  • Swine
  • Thrombin
  • Thrombosis/drug therapy
  • Ticks/genetics
  • Transcriptome

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