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• W4289767178 abstract "Abstract Gla-domainless factor Xa (GD-FXa) was proposed as a trap to the endogenous anticoagulant Tissue Factor Pathway Inhibitor (TFPI) to restore thrombin generation in hemophilia. Using computational chemistry and experimental approaches, we previously showed that S195A GD-FXa also binds TFPI and restores ex vivo coagulation in hemophilia plasmas. To design a GD-FXa variant with improved anti-TFPI activity and identify suitable sites for mutagenesis, we performed molecular dynamics simulations. The calculations identified residues R150 FXa and K96 FXa as cold-spots of interaction between GD-FXa and the K2 domain of TFPI. In the three-dimensional model, both residues are facing TFPI hydrophobic residues and are thus potential candidates for mutagenesis into hydrophobic residues to favor an improved protein-protein interaction. Catalytically inactive GD-FXa variants containing the S195A mutation and additional mutations as K96Y, R150I, R150G and R150F were produced to experimentally confirm these computational hypotheses. Among these mutants, the R150F FXA showed increased affinity for TFPI as theoretically predicted, and was also more effective than S195A GD-FXa in restoring coagulation in FVIII deficient plasmas. Moreover, the R150 mutants lost interaction with antithrombin, which is favorable to extend their half-life." @default.
• W4289767178 created "2022-08-04" @default.
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• W4289767178 date "2022-08-04" @default.
• W4289767178 modified "2023-09-24" @default.
• W4289767178 title "Rationally designed Gla-domainless FXa as TFPI bait in hemophilia" @default.
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• W4289767178 doi "https://doi.org/10.1101/2022.08.03.502629" @default.
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