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

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.

Cell‐Penetrable Lysine Dendrimers for Anti‐Cancer Drug Delivery: Synthesis and Preliminary Biological Evaluation

“…The application of cationic lysine dendrimers for delaying tumor growth have been reported by Khuloud and his co‐workers . Moreover, lysine dendrimers have been widely used as scaffold material of dendrimers , self‐assembling biomaterials , and carriers in drug delivery .…”

Molecular dynamics simulation of spin–lattice NMR relaxation in poly-l-lysine dendrimers: manifestation of the semiflexibility effect

“…[16][17][18] The relaxation properties of dendrimers are of considerable importance in many practical applications. [19][20][21][22][23] Even for a single dendrimer macromolecule, there are many relaxation processes with different lengths and time scales, starting from the rotation as a whole to the local segmental mobility. Different experimental methods are used to describe distinctive features of dendrimers (see e.g.…”

Solvent‐Assisted [(Glycine)‐(MP‐SiO2NPs)] Aggregate for Drug Loading and Cancer Therapy

“…To understand the morphology of cells, few fluorescent dyes such as FITC (fluorescent isothiocyanate), red fluorescent dye Rhodamine-B (Rho-B), and blue fluorescent dye DAPI were added to the components of K562 cells and [(Gly)-(MP-SiO 2 NPs)]-DOX aggregate. [42] Figure 9(a) corresponds to green fluorescent FITC which gives morphology and cell membrane, figure 9(b) corresponds to the bright field image of K562 cells. Figure 9(c) corresponds to red fluorescent Rho-B and it will also give the distribution of cell organelles and cell membrane, the figure 9(d) corresponds to overlay of images (a-c) which depicts the disrupted morphology of K562 cells.…”