A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase.
A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase.
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DOI：
10.1111/jth.15209
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Tie JK
中科院分区：
文献类型：
--
作者：
Chen X;Liu Y;Furukawa N;Jin DY;Paul Savage G;Stafford DW;Suhara Y;Williams CM;Tie JK
半个多世纪以来，华法林等维生素K拮抗剂(VKA)一直是口服抗凝治疗预防和治疗血栓栓塞症的基石。它们通过抑制维生素K环氧化物还原酶(VKOR)来损害维生素K依赖(VKD)凝血因子的生物合成。VKAS治疗的挑战是其治疗指标狭窄和剂量要求高度可变，这部分是由于VKOR的遗传变异。本研究的目的是寻找一种能耐受其靶酶遗传变异的改良VKA。合成了一系列1，4-萘醌的3位苯基及相应侧链取代的维生素K衍生物。这些化合物在VKD羧化中的作用通过基于哺乳动物细胞的检测和常规的体外活性检测来评估。我们的结果表明，用维生素K1 3位上的亚甲基环辛四烯(COT)部分取代植基侧链，使其从底物转变为VKD羧化的抑制剂。值得注意的是，这种Cot-维生素K衍生物在对华法林耐药的VKOR突变中显示出类似的抑制效力，其华法林耐药性变化超过400倍。Cot-维生素K抑制VKD羧化的进一步表征表明，该化合物针对维生素K氧化还原循环中的多个酶。重要的是，大剂量维生素K1可以挽救Cot-维生素K的抗凝作用。我们发现了一种维生素K类似物，它的功能是VKA，并且对靶酶的遗传变异具有耐受性。
Vitamin K antagonists (VKAs), such as warfarin, have remained the cornerstone of oral anticoagulation therapy in the prevention and treatment of thromboembolism for over 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 due to the genetic variations of VKOR. The goal of this study was to search for an improved VKA that is tolerant to the genetic variations of its target enzyme. 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. 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 over 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. We discovered a vitamin K analogue that functions as a VKA, and is tolerant to genetic variations in the target enzyme.
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影响因子：
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作者：
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通讯作者：
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