A PEPTIDE SEQUENCE FROM MOUSE-TISSUE FACTOR INHIBITS HUMAN TISSUE FACTOR-DEPENDENT FACTOR-X ACTIVATION

Synthetic peptides based on the putative factor X recognition site of human (Thr-Leu-Tyr-Tyr-Trp-Lys-Ser-Ser-Ser-Ser), rabbit (Thr-Leu-Tyr-T yr-Trp-Arg-Ala-Ser-Ser-Thr), and murine tissue factor (Ile-Ile-Thr-Tyr -Arg-Lys-Gly-Ser-Ser-Thr) were dose-dependent inhibitors of human tiss ue factor/factor VIIa catalyzed factor X activation with IC50 values o f 220, 17, and 33 mu M, respectively. The mouse results were highly su rprising given the low homology between the human and mouse sequence ( 40 %) and that mouse tissue factor, in contrast with rabbit tissue fac tor, does not support the procoagulant activity of human factor VIIa o n factor X. The inhibitory mechanism of the murine peptide was noncomp etitive with respect to factor X but competitive with respect to tissu e factor, indicating the peptide competes with tissue factor (or the t issue factor/factor VIIa complex) for binding to factor X. The peptide could be N-terminally truncated by two Ile without loss of inhibitory activity or changed inhibitory mechanism. Substitution of two Gly for the two Ile, which increased solubility, decreased IC50 to 17 mu M wh ereas scrambling the peptide made it inactive. (C) 1998 Elsevier Scien ce Ltd.