KRDS, a new peptide derived from human lactotransferrin, inhibits platelet aggregation and release reaction

Abstract

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 .mu.M] and fibrinogen binding (IC50 360 .mu.M) to a lesser extent than RGDS (IC50 75 .mu.M and 20 .mu.M, respectively). Different from RGDS, thrombin-induced serotonin release was inhibited by KRDS (750 .mu.M) 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.