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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F24%3A00598183" target="_blank" >RIV/61388971:_____/24:00598183 - isvavai.cz</a>
Alternative codes found
RIV/00216224:14740/24:00139985 RIV/61989592:15110/24:73626427 RIV/61989592:15640/24:73626427 RIV/65269705:_____/24:00080318
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00912" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00912</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jmedchem.4c00912" target="_blank" >10.1021/acs.jmedchem.4c00912</a>

Result language
angličtina
Original language name
Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities
Original language 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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10606 - Microbiology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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