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 Richards, R Manjunatha Kini, Mark Y Chan
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...
November 25, 2021: Nature Communications