2. Academic Validation
  3. Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities

Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities

  • J Med Chem. 2024 Aug 22;67(16):14040-14061. doi: 10.1021/acs.jmedchem.4c00912.
Rahul Deb 1 2,  Marcelo D T Torres 3 4 5 6,  Miroslav Boudný 1 7,  Markéta Koběrská 8,  Floriana Cappiello 9,  Miroslav Popper 10,  Kateřina Dvořáková Bendová 10,  Martina Drabinová 1,  Adelheid Hanáčková 1,  Katy Jeannot 11 12,  Miloš Petřík 10 13,  Maria Luisa Mangoni 9,  Gabriela Balíková Novotná 8,  Marek Mráz 1 7,  Cesar de la Fuente-Nunez 3 4 5 6,  Robert Vácha 1 2 14
Affiliations

Affiliations

  • 1 CEITEC - Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic.
  • 2 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic.
  • 3 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.
  • 4 Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 5 Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 6 Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 7 Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno 625 00, Czech Republic.
  • 8 Institute of Microbiology, Czech Academy of Sciences, BIOCEV, Vestec 252 50, Czech Republic.
  • 9 Department of Biochemical Sciences, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome 00185, Italy.
  • 10 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc 779 00, Czech Republic.
  • 11 University of Franche-Comté, CNRS, Chrono-environment, Besançon 25030, France.
  • 12 National Reference Centre for Antibiotic Resistance, Besançon 25030, France.
  • 13 Czech Advanced Technology and Research Institute, Palacký University, Olomouc 779 00, Czech Republic.
  • 14 Department of Condensed Matter Physics, Faculty of Science, Masaryk University, Brno 611 37, Czech Republic.
PMID: 39116273 DOI: 10.1021/acs.jmedchem.4c00912
Abstract

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.

Figures