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Title: Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors
Authors: Koh, Cho Yeow 
Shih, Norrapat 
Yip, Christina YC
Li, Aaron Wei Liang 
Chen, Weiming 
Amran, Fathiah S 
Leong, Esther Jia En 
Iyer, Janaki Krishnamoorthy
Croft, Grace 
Mazlan, Muhammad Ibrahim Bin
Chee, Yen-Lin 
Yap, Eng-Soo 
Monroe, Dougald M
Hoffman, Maureane
Becker, Richard C
de Kleijn, Dominique PV 
Verma, Vaishali
Gupta, Amita
Chaudhary, Vijay K
Richards, A Mark 
Kini, R Manjunatha 
Chan, Mark Y 
Issue Date: Dec-2021
Publisher: Springer Science and Business Media LLC
Citation: Koh, Cho Yeow, Shih, Norrapat, Yip, Christina YC, Li, Aaron Wei Liang, Chen, Weiming, Amran, Fathiah S, Leong, Esther Jia En, Iyer, Janaki Krishnamoorthy, Croft, Grace, Mazlan, Muhammad Ibrahim Bin, Chee, Yen-Lin, Yap, Eng-Soo, Monroe, Dougald M, Hoffman, Maureane, Becker, Richard C, de Kleijn, Dominique PV, Verma, Vaishali, Gupta, Amita, Chaudhary, Vijay K, Richards, A Mark, Kini, R Manjunatha, Chan, Mark Y (2021-12). Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors. Nature Communications 12 (1). ScholarBank@NUS Repository.
Abstract: AbstractDespite 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.
Source Title: Nature Communications
ISSN: 20411723
DOI: 10.1038/s41467-021-27275-8
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