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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Koh, CY; Shih, N; Yip, CYC; Li, AWL; Chen, W; Amran, FS; Leong, EJE; Iyer, JK; Croft, G; Mazlan, MIB; Chee, Y-L; Yap, E-S; Monroe, DM; Hoffman, M; Becker, RC; de Kleijn, DPV; Verma, V; Gupta, A; Chaudhary, VK; Richards, AM; Kini, RM; Chan, MY

Published Date

  • November 25, 2021

Published In

Volume / Issue

  • 12 / 1

Start / End Page

  • 6912 -

PubMed ID

  • 34824278

Pubmed Central ID

  • PMC8617063

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-27275-8

Language

  • eng

Conference Location

  • England