A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle.

摘要: Drug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended of obvious are relatively easy control. However, the mechanisms most drug-induced poorly understood, which makes intervention more difficult. As associated with dysfunction coagulation factors, we adapted our recently established cell-based assay identify drugs affect biosynthesis active vitamin K-dependent (VKD) factors possible adverse off-target results. The National Institutes Health (NIH) Clinical Collection (NCC) library containing 727 was screened, 9 were identified, including commonly prescribed anticoagulant warfarin. Bleeding complications these have been clinically reported, but pathogenic remain unclear. Further characterization top-hit on inhibition VKD carboxylation suggests warfarin, lansoprazole, nitazoxanide mainly target K epoxide reductase (VKOR), whereas idebenone, clofazimine, AM404 (VKR) in redox cycling. other 3 availability within cells. molecular underlying inactivation VKOR VKR by clarified. Results from both animal model studies suggest anticoagulation effect VKOR, not VKR, can be rescued administration K. These findings provide insights into prevention management disorders. cell-based, high-throughput screening approach provides a powerful tool for identifying new antagonists function as anticoagulants.