A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase

Xuejie Chen, Yizhou Liu, Natsuko Furukawa, Da Yun Jin, G. Paul Savage, Darrel W. Stafford, Yoshitomo Suhara, Craig M. Williams, Jian Ke Tie

研究成果: Article査読

5 被引用数 (Scopus)


Background: Vitamin K antagonists (VKAs), such as warfarin, have remained the cornerstone of oral anticoagulation therapy in the prevention and treatment of thromboembolism for more than half a century. They function by impairing the biosynthesis of vitamin K-dependent (VKD) clotting factors through the inhibition of vitamin K epoxide reductase (VKOR). The challenge of VKAs therapy is their narrow therapeutic index and highly variable dosing requirements, which are partially the result of genetic variations of VKOR. Objectives: The goal of this study was to search for an improved VKA that is tolerant to the genetic variations of its target enzyme. Methods: A series of vitamin K derivatives with benzyl and related side-chain substitutions at the 3-position of 1,4-naphthoquinone were synthesized. The role of these compounds in VKD carboxylation was evaluated by mammalian cell-based assays and conventional in vitro activity assays. Results: Our results showed that replacing the phytyl side-chain with a methylene cyclooctatetraene (COT) moiety at the 3-position of vitamin K1 converted it from a substrate to an inhibitor for VKD carboxylation. Strikingly, this COT-vitamin K derivative displayed a similar inhibition potency in warfarin-resistant VKOR mutations whose warfarin resistance varied more than 400-fold. Further characterization of COT-vitamin K for the inhibition of VKD carboxylation suggested that this compound targets multiple enzymes in the vitamin K redox cycle. Importantly, the anticoagulation effect of COT-vitamin K can be rescued with high doses of vitamin K1. Conclusion: We discovered a vitamin K analogue that functions as a VKA and is tolerant to genetic variations in the target enzyme.

ジャーナルJournal of Thrombosis and Haemostasis
出版ステータスPublished - 2021 3月

ASJC Scopus subject areas

  • 血液学


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