Synthesis and inhibition study on tripeptide inhibitor modified poly(L-lysine) dendrimers

J Biomater Appl. 2012 Jul;27(1):17-26. doi: 10.1177/0885328210386821. Epub 2010 Dec 1.

Abstract

Peptide dendrimers are attractive nonviral gene vectors. But a biological barrier for their application in gene delivery is the fast degradation catalyzed by proteasomes. Proteasome inhibitors are efficient at prohibiting the degradation of peptide nonviral vectors, thus enhancing gene transfection efficiency. In this study, N(α)-Boc-protected leucine vinyl ester proteasome inhibitor Boc-Leu-Leu-Leu-ve was synthesized by the liquid-phase method and was then immobilized onto poly(L-lysine) dendrimers. Suc-Leu-Leu-Val-Tyr-AMC was used as fluorimetric substrate and the inhibition capacity of Boc-Leu-Leu-Leu-ve immobilized onto G(3) and G(6) poly(L-lysine) dendrimers for the chymotrypsin-like activity of ACHN cell proteasome was tested. The results indicated that both Boc-Leu-Leu-Leu-ve peptide and the peptide immobilized on G(3) dendrimer showed low inhibition capacity when the concentration was below 0.2 μM. When the inhibitor concentrations were increased to 5.0 μM, however, the percentage inhibition of Boc-Leu-Leu-Leu-ve peptide and the peptide immobilized on G(3) dendrimer became about 50% and 25%, and that of peptide immobilized on the G(6) dendrimer was 7.5% only. These results indicated that dendritic structure and linker length could be the main factors affecting proteasome inhibition capacity. The cytotoxicity of the dendritic inhibitors was found to be low. Thus, whilst the synthetic production of poly(L-lysine) dendrimers immobilized with peptide inhibitors was successful and these modified dendrimers could work to inhibit proteasome activity, further studies will need to be carried out to improve inhibition capacity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dendrimers / chemical synthesis*
  • Dendrimers / chemistry
  • Dendrimers / pharmacology
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mice
  • NIH 3T3 Cells
  • Oligopeptides / chemistry*
  • Polylysine / chemistry*
  • Proteasome Inhibitors
  • Spectrometry, Mass, Electrospray Ionization
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Dendrimers
  • Enzyme Inhibitors
  • Oligopeptides
  • Proteasome Inhibitors
  • Polylysine