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Toward non-factor therapy in hemophilia: an antithrombin insensitive Gla-domainless factor Xa as tissue factor pathway inhibitor bait. | LitMetric

AI Article Synopsis

  • Researchers explored modifying Gla-domainless factor Xa (GD-FXa) to better bind the tissue factor pathway inhibitor (TFPI), aiming to enhance thrombin generation in hemophilia patients.* -
  • Molecular dynamics simulations helped identify key residues R150 and K96 for mutation, leading to the development of various GD-FXa variants that were tested for their effectiveness in restoring coagulation.* -
  • Some variants (R150F and K96YR150F) showed improved thrombin generation rates but maintained similar TFPI binding affinities, suggesting that their resistance to antithrombin contributed to their effectiveness.*

Article Abstract

Background: Gla-domainless factor (F) Xa (GD-FXa) was proposed as a trap to 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 coagulation in plasma obtained from person(s) with hemophilia.

Methods: To design a GD-FXa variant with improved anti-TFPI affinity, we performed molecular dynamics simulations and identified suitable sites for mutagenesis. The calculations identified residues R150 and K96 as cold-spots of interaction between GD-FXa and the K2 domain of TFPI. In the three-dimensional model, both residues face toward TFPI hydrophobic residues and are thus potential candidates for mutagenesis into hydrophobic residues to favor an improved protein-protein interaction.

Results: Catalytically inactive GD-FXa variants containing the S195A mutation and the additional mutations K96Y, R150I, R150G, R150F, and K96YR150F, were produced to experimentally confirm these computational hypotheses. Among these mutants, the R150F and the K96YR150F were slightly more effective than S195A GD-FXa in restoring coagulation in FVIII deficient plasmas. However, in surface plasmon resonance experiments, they showed TFPI binding affinities in the same range and acted similarly as S195A GD-FXa in FXa/TFPI competition assays. In contrast, the R150 mutants completely lost their interactions with antithrombin as observed in the surface plasmon resonance experiments.

Conclusions: We therefore conclude that their antithrombin resistance is responsible for their improved thrombin generation, through an extension of their half-lives.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568284PMC
http://dx.doi.org/10.1016/j.rpth.2023.102175DOI Listing

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