KRDS, a new peptide derived from human lactotransferrin, inhibits platelet aggregation and release reaction.
KRDS (Lys-Arg-Asp-Ser), a tetrapeptide from human lactotransferrin, was tested in vitro on human platelet function, and its effects were compared to those of RGDS, a tetrapeptide from human fibrinogen. Both peptides had a high probability of initiating a beta-turn and were highly hydrophilic. KRDS inhibited ADP-induced platelet aggregation [median inhibitory concentration (IC50) 350 microM] and fibrinogen binding (IC50 360 microM) to a lesser extent than RGDS (IC50 75 microM and 20 microM, respectively). Different from RGDS, thrombin-induced serotonin release was inhibited by KRDS (750 microM) on normal platelets (55 +/- 10%) and type I Glanzmann's thrombasthenia platelets (43% +/- 1). However, KRDS had no effect on cytoplasmic Ca2+ mobilization, inositol phospholipid metabolism or protein phosphorylation (myosin light chain P20 and P43). In contrast to RGDS, KRDS does not inhibit the binding of monoclonal antibody PAC-1 to activated platelets. KRDS and RGDS inhibited 4 beta-phorbol-12-myristate-13-acetate (PMA)-induced aggregation and fibrinogen binding, while proteins were normally phosphorylated. Thus, the tetrapeptide KRDS is (a) an inhibitor of serotonin release by a mechanism independent of protein phosphorylation and (b) an inhibitor of fibrinogen binding and, hence, aggregation by a mechanism that may not necessarily involve its direct binding to the glycoprotein IIb-IIIa-complex.
Mazoyer
E
E
Institut des Vaisseaux et du Sang, Paris, France.
Lévy-Toledano
S
S
Rendu
F
F
Hermant
L
L
Lu
H
H
Fiat
A M
AM
Jollès
P
P
Caen
J
J
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D001792:Blood Platelets / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D066298:In Vitro Techniques; D007781:Lactoferrin / Q000138:chemical synthesis / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011487:Protein Conformation; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D009842:Oligopeptides; D010446:Peptide Fragments; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C056549:KRDS peptide; D012701:Serotonin; D000244:Adenosine Diphosphate; D005340:Fibrinogen; C046617:arginyl-glycyl-aspartyl-serine; D007781:Lactoferrin; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium