Synthetic peptide analogs of tissue factor and factor VII which inhibit factor Xa formation by the tissue factor/factor VIIa complex.
Factor VII (FVII) and tissue factor (TF) form a binary complex which initiates the extrinsic pathway of the blood coagulation cascade. The infrequent tripeptide motif Trp-Lys-Ser (WKS) is found three times in TF. It has been suggested that the motif is involved in binding of TF to FVII(a). Also. Lys165 and Lys166 of TF have been reported to be important for factor X activation. To elucidate the molecular interactions between TF and FVIIa, and the interactions between the binary complex and FX, we examined the inhibitory effect of synthetic TF and FVII peptide analogs. One- and two-stage chromogenic assays were employed, as well as one-stage coagulation assay. The peptide analogs of TF possessed the WKS motif, the double lysine residues or other regions of TF. Synthetic peptides of FVII encompassing sequences of the FVII285-305 region were included for comparative purposes. TF154-167 and FVII300-305 significantly inhibited both FX activation and plasma coagulation. FVII285-294 acted synergistically, increasing that effect observed by FVII300-305 on FX activation. However, TF163-175 possessing the double lysine residues did not inhibit FX activation, indicating that inhibition of FXa formation and coagulation by TF154-167 is due to the region 154-162 of TF. None of the peptides, including the WKS tripeptide, interfered with the FVIIa activity of the TF/FVIIa complex. Thus, the results do not suggest that the WKS motifs are necessary for binding of TF to FVIIa but that the third WKS motif may be of importance for the activation of FX.
Rønning
H F
HF
Department of Biochemistry/Biotechnology Centre, University of Oslo, Norway.
Risøen
U C
UC
Orning
L
L
Sletten
K
K
Sakariassen
K S
KS
D005167:Factor VII / Q000737:chemistry / Q000494:pharmacology*; D015942:Factor VIIa / Q000378:metabolism* / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013925:Thromboplastin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D065427:Factor Xa Inhibitors; D010455:Peptides; D005167:Factor VII; D013925:Thromboplastin; D015942:Factor VIIa