Abstract
This review focuses on the validation of the principal initiator of human coagulation, the tissue factor (TF)/coagulation factor (F)VIIa complex, as an antithrombotic target, as well as on the discovery of a cyclic pentapeptide (PN7051), which dose-dependently inhibits TF/FVIIa-induced coagulation and thrombus formation. Target validation and studies of antithrombotic efficacy were performed with a human thrombosis model employing non-anticoagulated blood from severe homozygous FVII-deficient patients and healthy individuals at blood-flow conditions mimicking those in healthy and diseased vessels. Additional validation included an anti-TF monoclonal antibody, recombinant TF pathway inhibitor, recombinant inactivated-active site FVIIa and all-trans retinoic acid. Structural and biological characterization of PN7051 and other peptides from the same FVII domain indicate that PN7051 interferes with an essential interaction between the epidermal growth factor domain-2-like and the catalytic domains of FVIIa. A peptidomimetics approach is suggested to further improve the antithrombotic potency of PN7051.
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