Publication details

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

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Authors

DEB Rahul TORRES Marcelo D T BOUDNÝ Miroslav KOBERSKA Marketa CAPPIELLO Floriana POPPER Miroslav DVORAKOVA BENDOVA Katerina DRABINOVÁ Martina HANACKOVA Adelheid JEANNOT Katy PETRIK Milos MANGONI Maria Luisa BALIKOVA NOVOTNA Gabriela MRÁZ Marek DE LA FUENTE-NUNEZ Cesar VÁCHA Robert

Year of publication 2024
Type Article in Periodical
Magazine / Source Journal of Medicinal Chemistry
MU Faculty or unit

Central European Institute of Technology

Citation
web https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00912
Doi http://dx.doi.org/10.1021/acs.jmedchem.4c00912
Attached files
Description 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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