Bioorganic & medicinal chemistry

Synthesis, nano-scale assembly, and in vivo anti-thrombotic activity of novel short peptides containing L-Arg and L-Asp or L-Glu.

PMID 18495483


Two tripeptides H-Asp(Arg)-Arg (3a) and H-Glu(Arg)-Arg (3b), four pentapeptides H-Asp(Arg-Asp)-Arg-Asp (6a), H-Glu(Arg-Asp)-Arg-Asp (6b), H-Asp(Asp- Arg)-Asp-Arg (10a), and H-Glu(Asp-Arg)-Asp-Arg (10b), and their Cu(II)-peptide complexes Cu(II)-Asp(Arg)-Arg [3a-Cu(II)], Cu(II)-Glu(Arg)-Arg [3b-Cu(II)], Cu(II)-Asp(Arg-Asp)-Arg-Asp [6a-Cu(II)], Cu(II)-Glu(Arg-Asp)-Arg-Asp [6b-Cu(II)], Cu(II)-Asp(Asp-Arg)-Asp-Arg [10a-Cu(II)], and Cu(II)-Glu(Asp-Arg)-Asp-Arg [10b-Cu(II)] were designed and synthesized. Their self-assembling properties and in vivo anti-thrombotic activities were investigated. In normal saline (NS), the Cu(II)-peptide complexes assembled into stable nano-particles surrounded by negative charges (-4.102 to -9.825mV), with diameters ranging from 212.1+/-4.0 to 632.4+/-36.7nm. TEM analysis exhibited that the compounds remained as nano-globes in the solid state, with diameters ranging from 15 to 20nm. In an in vivo anti-thrombotic assay, peptides (3,6,10)a,b at 5micromol/kg reduced the thrombus weights of a rat model by 15-40%. Aspirin, a widely used anti-thrombotic drug, achieved comparable activity in this model system at a dosage of ca. 110micromol/kg. The required dosage of Cu(II)-peptide complexes [(3,6,10)a,b]-Cu(II), which assemble into stable nano-particles, was significantly reduced to 0.05micromol/kg. Therefore, the anti-thrombotic activity of the nano-particles [(3,6,10)a,b]-Cu(II) increased dramatically by 100-fold over that of the corresponding peptides.