Synthesis, nano-scale assembly, and in vivo anti-thrombotic activity of novel short peptides containing L-Arg and L-Asp or L-Glu.
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.
Chen
Yu
Y
College of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China.
Cui
Guohui
G
Zhao
Ming
M
Wang
Chao
C
Qian
Keduo
K
Morris-Natschke
Susan
S
Lee
Kuo-Hsiung
KH
Peng
Shiqi
S
D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001224:Aspartic Acid / Q000737:chemistry*; D001241:Aspirin / Q000008:administration & dosage; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D018698:Glutamic Acid / Q000737:chemistry*; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis*; D010316:Particle Size; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis*; D051381:Rats; D013927:Thrombosis / Q000175:diagnosis / Q000378:metabolism / Q000517:prevention & control
D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D001224:Aspartic Acid; D018698:Glutamic Acid; D001120:Arginine; D001241:Aspirin