Evaluation of oral anticoagulants with vitamin K epoxide reductase in its native milieu

Chen, Xuejie; Jin, Da-Yun; Stafford, Darrel W.; Tie, Jian Ke

doi:10.1182/blood-2018-05-846592

Cited by 29 publications

(32 citation statements)

References 60 publications

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“…Therefore, warfarin should be competitive with substrates at the PO state, but not competitive at the O or R states. This difference explains the previous observation that warfarin is a mixed inhibitor showing a combination of noncompetitive and competitive kinetics (15,16).…”

Section: Discussionmentioning

confidence: 51%

The catalytic mechanism of vitamin K epoxide reduction in a cellular environment

Shen

Cui

Cao

et al. 2021

Journal of Biological Chemistry

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Vitamin K epoxide reductases (VKORs) constitute a major family of integral membrane thiol oxidoreductases. In humans, VKOR sustains blood coagulation and bone mineralization through the vitamin K cycle. Previous chemical models assumed that the catalysis of human VKOR (hVKOR) starts from a fully reduced active site. This state, however, constitutes only a minor cellular fraction (5.6%). Thus, the mechanism whereby hVKOR catalysis is carried out in the cellular environment remains largely unknown. Here we use quantitative mass spectrometry (MS) and electrophoretic mobility analyses to show that KO likely forms a covalent complex with a cysteine mutant mimicking hVKOR in a partially oxidized state. Trapping of this potential reaction intermediate suggests that the partially oxidized state is catalytically active in cells. To investigate this activity, we analyze the correlation between the cellular activity and the cellular cysteine status of hVKOR. We find that the partially oxidized hVKOR has considerably lower activity than hVKOR with a fully reduced active site. Although there are more partially oxidized hVKOR than fully reduced hVKOR in cells, these two reactive states contribute about equally to the overall hVKOR activity, and hVKOR catalysis can initiate from either of these states. Overall, the combination of MS quantification and biochemical analyses reveals the catalytic mechanism of this integral membrane enzyme in a cellular environment. Furthermore, these results implicate how hVKOR is inhibited by warfarin, one of the most commonly prescribed drugs.

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Section: Discussionmentioning

confidence: 51%

The catalytic mechanism of vitamin K epoxide reduction in a cellular environment

Shen

Cui

Cao

et al. 2021

Journal of Biological Chemistry

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“…As shown in Table S1, there were two exceptions to this rule. For study NCT02546167 (CART-BCMA UPenn), we decided to use the full publication [ 20 ] rather than the meeting abstract [ 21 ]. For study NCT03661554 (BCMA nanoantibody), the latest publication involving 16 CAR-T-infused patients was not considered because outcome data were incompletely reported (only for 7 patients) [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

et al. 2020

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Background B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes. Methods We performed a database search using the terms “BCMA,” “CAR,” and “multiple myeloma” for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332). Results Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0–88.2); 10.5% (6.8–16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3–26.7; I2 = 45%) versus 2.8% (1.3–6.1; I2 = 0%) (p < 0.0001). The pooled overall response rate was 80.5% (73.5–85.9); complete responses (CR) were observed in 44.8% (35.3–54.6). A pooled CR rate of 71.9% (62.8–79.6; I2 = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5–41.1; I2 = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4–17.4) months, which compared favorably to the expected PFS of 1.9 (1.5–3.7) months (HR 0.14; p < 0.0001). Conclusions Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

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“…A subsequent evaluation showed that the ( S )‐enantiomer of COT‐warfarin was four‐fold more potent than the ( R )‐enantiomer (see the Supporting Information, Figure S5). Considering that the genetic variation in the VKOR gene is one of the largest factors contributing to the difficulty in the clinical use of warfarin, the performance of the racemic COT analogue ( 8 ) was explored against the 27 naturally occurring human VKOR mutants by using VKOR/VKORC1L1 double gene knockout reporter cells ,. It was found that 8 and warfarin displayed a similar pattern of resistance to all naturally occurring VKOR mutants, suggesting they might bind to the same site in VKOR.…”

Section: Methodsmentioning

confidence: 99%

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement

Xing

Houston

Chen

et al. 2019

Chemistry A European J

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Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

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Evaluation of oral anticoagulants with vitamin K epoxide reductase in its native milieu

Abstract: Key Points Acenocoumarol is the most efficient oral anticoagulant with the least variation of resistance among naturally occurring VKOR mutations. Warfarin and fluindione are equipotent for anticoagulation control but have different mechanisms of action on VKOR inactivation.

Cited by 29 publications

References 60 publications

The catalytic mechanism of vitamin K epoxide reduction in a cellular environment

The catalytic mechanism of vitamin K epoxide reduction in a cellular environment

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement

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