Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity
| Autor: | Joshua Grabeck, Andre Reinhardt, Tom Cronenberg, Frank Nitsche, Berenike Maier, Pitter F. Huesgen, Ines Neundorf, Marco Drexelius |
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| Rok vydání: | 2020 |
| Předmět: |
Halogenation
Cell Survival Antimicrobial peptides Cell Antineoplastic Agents Cell-Penetrating Peptides Microbial Sensitivity Tests Pseudomonas fluorescens 01 natural sciences Biochemistry Hemolysis Cell membrane 03 medical and health sciences Inhibitory Concentration 50 Cell Line Tumor medicine Humans Molecular Biology 030304 developmental biology 0303 health sciences Bacteria 010405 organic chemistry Chemistry Circular Dichroism Cell Membrane Cell Biology Antimicrobial 0104 chemical sciences Anti-Bacterial Agents Multiple drug resistance Corynebacterium glutamicum Micrococcus luteus medicine.anatomical_structure ddc:540 Cancer cell Cell-penetrating peptide Microscopy Electron Scanning Antibacterial activity Hydrophobic and Hydrophilic Interactions Antimicrobial Cationic Peptides Bacillus subtilis |
| Zdroj: | Biochemical journal 478(1), 63-78 (2021). doi:10.1042/BCJ20200698 |
| ISSN: | 1470-8728 |
| DOI: | 10.1042/BCJ20200698 |
| Popis: | Multidrug resistant (MDR) bacteria have adapted to most clinical antibiotics and are a growing threat to human health. One promising type of candidates for the everlasting demand of new antibiotic compounds constitute antimicrobial peptides (AMPs). These peptides act against different types of microbes by permeabilizing pathogen cell membranes, whereas being harmless to mammalian cells. Contrarily, another class of membrane-active peptides, namely cell-penetrating peptides (CPPs), is known to translocate in eukaryotic cells without substantially affecting the cell membrane. Since CPPs and AMPs share several physicochemical characteristics, we hypothesized if we can rationally direct the activity of a CPP towards antimicrobial activity. Herein, we describe the screening of a synthetic library, based on the CPP sC18, including structure-based design to identify the active residues within a CPP sequence and to discover novel AMPs with high activity. Peptides with increased hydrophobicity were tested against various bacterial strains, and hits were further optimized leading to four generations of peptides, with the last also comprising fluorinated amino acid building blocks. Interestingly, beside strong antibacterial activities, we also detected activity in cancer cells, while non-cancerous cells remained unharmed. The results highlight our new candidates, particularly those from generation 4, as a valuable and promising source for the development of future therapeutics with antibacterial activity and beyond. |
| Databáze: | OpenAIRE |
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