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. Kleijn, Vaishali Verma, Amita Gupta, Vijay K. Chaudhary, A. Mark Richards, R. Manjunatha Kini () and Mark Y. Chan ()
Additional contact information
Cho Yeow Koh: National University of Singapore
Norrapat Shih: National University of Singapore
Christina Y. C. Yip: National University Hospital
Aaron Wei Liang Li: National University of Singapore
Weiming Chen: National University of Singapore
Fathiah S. Amran: National University of Singapore
Esther Jia En Leong: National University of Singapore
Janaki Krishnamoorthy Iyer: National University of Singapore
Grace Croft: National University of Singapore
Muhammad Ibrahim Bin Mazlan: National University of Singapore
Yen-Lin Chee: National Cancer Institute
Eng-Soo Yap: National Cancer Institute
Dougald M. Monroe: University of North Carolina at Chapel Hill
Maureane Hoffman: Duke University
Richard C. Becker: University of Cincinnati
Dominique P. V. Kleijn: National University of Singapore
Vaishali Verma: University of Delhi South Campus
Amita Gupta: University of Delhi South Campus
Vijay K. Chaudhary: University of Delhi South Campus
A. Mark Richards: NUHS
R. Manjunatha Kini: National University of Singapore
Mark Y. Chan: National University of Singapore

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27275-8

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