ABSTRACT
A new category of phosphonium based cationic amphiphilic peptides has been developed and evaluated as potential antimicrobial peptides and cell penetrating peptides. The required building blocks were conveniently accessible from cysteine and could be applied in a solid phase peptide synthesis protocol for incorporation into peptide sequences. Evaluation of the antimicrobial properties and cellular toxicity of these phosphonium based peptides showed that these "soft" cationic side-chain containing peptides have poor antimicrobial properties and most of them were virtually non toxic (on HEK cells tested at 256 and 512 µM) and non-haemolytic (on horse erythrocytes tested at 512 µM), hinting at an interesting potential application as cell penetrating peptides. This possibility was evaluated using fluorescent peptide derivatives and showed that these phosphonium based peptide derivatives were capable of entering HEK cells and depending on the sequence confined to specific cellular areas.
ABSTRACT
A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivatives as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the ß2 subunit over that of the ß5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compounds are slightly more selective for inhibition of the constitutive over the immunoproteasome.
