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Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities
R. Deb, MDT. Torres, M. Boudný, M. Koběrská, F. Cappiello, M. Popper, K. Dvořáková Bendová, M. Drabinová, A. Hanáčková, K. Jeannot, M. Petřík, ML. Mangoni, G. Balíková Novotná, M. Mráz, C. de la Fuente-Nunez, R. Vácha
Language English Country United States
Document type Journal Article
Grant support
R35 GM138201
NIGMS NIH HHS - United States
- MeSH
- Acinetobacter baumannii drug effects MeSH
- Anti-Bacterial Agents pharmacology chemistry chemical synthesis MeSH
- Antimicrobial Peptides chemistry pharmacology chemical synthesis MeSH
- Antimicrobial Cationic Peptides pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Design * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Peptides that form transmembrane barrel-stave pores are potential alternative therapeutics for bacterial infections and cancer. However, their optimization for clinical translation is hampered by a lack of sequence-function understanding. Recently, we have de novo designed the first synthetic barrel-stave pore-forming antimicrobial peptide with an identified function of all residues. Here, we systematically mutate the peptide to improve pore-forming ability in anticipation of enhanced activity. Using computer simulations, supported by liposome leakage and atomic force microscopy experiments, we find that pore-forming ability, while critical, is not the limiting factor for improving activity in the submicromolar range. Affinity for bacterial and cancer cell membranes needs to be optimized simultaneously. Optimized peptides more effectively killed antibiotic-resistant ESKAPEE bacteria at submicromolar concentrations, showing low cytotoxicity to human cells and skin model. Peptides showed systemic anti-infective activity in a preclinical mouse model of Acinetobacter baumannii infection. We also demonstrate peptide optimization for pH-dependent antimicrobial and anticancer activity.
CEITEC Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic
Czech Advanced Technology and Research Institute Palacký University Olomouc 779 00 Czech Republic
Institute of Microbiology Czech Academy of Sciences BIOCEV Vestec 252 50 Czech Republic
National Reference Centre for Antibiotic Resistance Besançon 25030 France
University of Franche Comté CNRS Chrono environment Besançon 25030 France
References provided by Crossref.org
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- $a Peptides that form transmembrane barrel-stave pores are potential alternative therapeutics for bacterial infections and cancer. However, their optimization for clinical translation is hampered by a lack of sequence-function understanding. Recently, we have de novo designed the first synthetic barrel-stave pore-forming antimicrobial peptide with an identified function of all residues. Here, we systematically mutate the peptide to improve pore-forming ability in anticipation of enhanced activity. Using computer simulations, supported by liposome leakage and atomic force microscopy experiments, we find that pore-forming ability, while critical, is not the limiting factor for improving activity in the submicromolar range. Affinity for bacterial and cancer cell membranes needs to be optimized simultaneously. Optimized peptides more effectively killed antibiotic-resistant ESKAPEE bacteria at submicromolar concentrations, showing low cytotoxicity to human cells and skin model. Peptides showed systemic anti-infective activity in a preclinical mouse model of Acinetobacter baumannii infection. We also demonstrate peptide optimization for pH-dependent antimicrobial and anticancer activity.
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