Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities.
Rahul DebMarcelo D T TorresMiroslav BoudnýMarkéta KoběrskáFloriana CappielloMiroslav PopperKateřina Dvořáková BendováMartina DrabinováAdelheid HanáčkováKaty JeannotMilos PetrikMaria Luisa MangoniGabriela Balíková NovotnáMarek MrázCesar de la Fuente-NunezRobert VáchaPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- acinetobacter baumannii
- atomic force microscopy
- amino acid
- mouse model
- multidrug resistant
- staphylococcus aureus
- high speed
- papillary thyroid
- small molecule
- squamous cell carcinoma
- molecular dynamics
- single molecule
- risk assessment
- machine learning
- cystic fibrosis
- climate change
- soft tissue
- squamous cell
- high resolution
- mass spectrometry