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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
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
R35 GM138201
NIGMS NIH HHS - United States
- MeSH
- Acinetobacter baumannii účinky léků MeSH
- antibakteriální látky farmakologie chemie chemická syntéza MeSH
- antimikrobiální peptidy chemie farmakologie chemická syntéza MeSH
- kationické antimikrobiální peptidy farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- racionální návrh léčiv * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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
Citace poskytuje Crossref.org
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- $a Deb, Rahul $u CEITEC - Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic $u National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic $1 https://orcid.org/0000000227337012
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- $a Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities / $c 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
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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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- $a Torres, Marcelo D T $u Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States $u Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States $u Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States $u Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
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- $a Boudný, Miroslav $u CEITEC - Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno 625 00, Czech Republic
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- $a Koběrská, Markéta $u Institute of Microbiology, Czech Academy of Sciences, BIOCEV, Vestec 252 50, Czech Republic $1 https://orcid.org/0000000297874227
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- $a Drabinová, Martina $u CEITEC - Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic
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- $a Hanáčková, Adelheid $u CEITEC - Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic
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- $a Petřík, Miloš $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc 779 00, Czech Republic $u Czech Advanced Technology and Research Institute, Palacký University, Olomouc 779 00, Czech Republic $1 https://orcid.org/0000000313345916
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- $a Vácha, Robert $u CEITEC - Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic $u National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic $u Department of Condensed Matter Physics, Faculty of Science, Masaryk University, Brno 611 37, Czech Republic $1 https://orcid.org/000000017610658X
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