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Synthese en toepassing van een lipofiel aminozuurderivaat voor het verbeteren van de membraanaffiniteit van antimicrobiële peptiden
| Content Provider | Semantic Scholar |
|---|---|
| Author | Slootweg, J. Chris Schaik, Timo B. Van Ufford, H. C. Quarles Breukink, Eefjan Liskamp, Rob M. J. Rijkers, Dirk T. S. |
| Copyright Year | 2014 |
| Abstract | OBJECTIVE: To increase the potential of membrane-acting peptides as possible novel drug-like compounds by increasing lipophilicity and thereby enhancing membrane affinity. DESIGN: An Fmoc-protected enantiomerically pure lipophilic amino acid (Fmoc-Lad-OH), which contains a nine carbon atom hydrophobic side chain, was designed. Fmoc-Lad-OH can be introduced into any peptide sequence using standard solid phase peptide synthesis to increase the lipophilicity of a peptide without sacrificing important polar segments of a peptide like for instance the N and C-termini. The antimicrobial decapeptide anoplin was chosen as a model peptide to test the hypothesis. METHODS: Fmoc-Lad-OH was prepared via organic synthesis and incorporated into the anoplin peptide sequence using solid-phase peptide synthesis followed by reversed-phase HPLC purification. Biological activity was evaluated using microtiter dilution bacterial growth assays, haemolytic assays and membrane vesicle leakage experiments. RESULTS: All three lipophilic analogues show a dramatic increase in antimicrobial activity: up to 4-8 times better for Escherichia coli (Gram-negative] and over one order of magnitude for Staphylococcus aureus (Gram-positive) compared to anoplin. Although the haemolytic activity was increased for the lipophilic analogues, the concentration at which 50% lysis will occur (EC50) was still one order of magnitude higher than the determined MICs. In the membrane vesicle leakage experiments the lipophilic analogues showed a higher lytic activity than anoplin, in agreement with the observed MIC values. CONCLUSION: Introduction of Lad into anoplin clearly showed a positive effect, which suggests that Fmoc-Lad-OH could be used as a general approach to increase membrane affinity of membrane-acting peptides. |
| Starting Page | 174 |
| Ending Page | 179 |
| Page Count | 6 |
| File Format | PDF HTM / HTML |
| Volume Number | 149 |
| Alternate Webpage(s) | https://www.npfo.nl/assets/archive_item/pdf/0d5addd6e5ea469d1494d9da7e8d88ac_2014wp0174.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
