Title : Modification of peptides to increase their cellular uptake
Abstract:
Cell-penetrating peptides may be useful tools in drug delivery, however they have some limitations. These limitations; low stability, endosomatic internalisation and thus the vesicular entrapment reduce their applicability. Thus there is high effort to improve their biochemical properties. In this presentation some chemical modifications will be shown which can be applied to increase the direct translocation of peptides through the cell membrane, thus enhance the effectiveness of peptides as delivery agent. We described that 4–((4–(dimethylamino)phenyl)azo)benzoyl) (Dabcyl) group, a well-known chromophore used in FRET system, may enhance the internalisation of positively charged non cell-permeable peptides. This new derivative was more efficient than octaarginine a well-known cell-penetrating peptide. Its increased internalisation resulted in higher accumulation in the cytosol. Its conjugates with antitumor drugs showed the same or better activity than the same conjugates of octaarginine. While the octaarginine could not deliver efficiently the methotrexate our new construct could and this conjugates was active on resistant breast cancer cells. Using Dabcyl group and the introduction of Arg residues we could increase the cellular uptake of a peptide without losing the biological activity. This peptide can bind to the Mitogen-Activated Protein Kinase (MAPK) docking groove and thus inhibit the protein-protein interaction of MAPK and their substrate or kinases. Further optimisation decreased its size and its stability might be enhanced by cyclisation. Its cyclic or bicyclic derivatives showed good or better binding to the MAPK. The presented examples highlight the possibility of chemical modification of peptides to increase their activity and/or stability.
