A peptide sequence from the EGF-2 like domain of FVII inhibits TF-dependent FX activation

Thrombosis Research
Lars OrningK S Sakariassen

Abstract

We have found that synthetic peptides derived from the two epidermal growth factor-like domains of factor VII are inhibitors of tissue factor dependent factor X activation. Inhibition was most pronounced for a constrained sequence of amino acids corresponding to positions 91-102 of factor VII, Cys-Val-Asn-Glu-Asn-Gly-Gly-Cys-Glu-Gin-Tyr-Cys. The biological activity appeared to be localized to the tripeptide 'motif', Glu-Gln-Tyr, within the larger sequence. The cyclic peptide was also an inhibitor of tissue factor induced coagulation of plasma, using lipidated tissue factor or tissue factor expressed on the surface of living cells. However, it did not interfere with intrinsic coagulation. Inhibition of factor X activation was dose-dependent with an IC50 value of 350 microM. Kinetic analyses revealed non-competitive inhibition with respect to factor X and suggested that the peptide sequence interferes with the factor VII/tissue factor/factor X complex formation and function. A pentapeptide analog of the putative pharmacophore was also a dose-dependent inhibitor of factor X activation with an IC50 value of 560 microM, but the tripeptide, Glu-Gin-Tyr, alone was without effect. Our results suggest a direct role for the second epider...Continue Reading

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Citations

Mar 27, 2002·Journal of Computational Chemistry·Lalith PereraLee G Pedersen
May 20, 1998·American Heart Journal·S R Hanson, K S Sakariassen
May 12, 2012·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Hye In WooHee-Jin Kim
Jul 5, 2001·The Journal of Peptide Research : Official Journal of the American Peptide Society·C K HuP M Fischer
Jan 24, 1998·The Journal of Peptide Research : Official Journal of the American Peptide Society·M HusbynP M Fischer

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