RpoN-Based stapled peptides with improved DNA binding suppress Pseudomonas aeruginosa virulence.
André R PaquetteSterling R PayneGeoffrey A McKayJordan T Brazeau-HenrieMicheal G DarnowskiAnitha KammiliFederico BernalThien-Fah MahSamantha GruenheidDao NguyenChristopher N BoddyPublished in: RSC medicinal chemistry (2022)
Stapled peptides have the ability to mimic α-helices involved in protein binding and have proved to be effective pharmacological agents for disrupting protein-protein interactions. DNA-binding proteins such as transcription factors bind their cognate DNA sequences via an α-helix interacting with the major groove of DNA. We previously developed a stapled peptide based on the bacterial alternative sigma factor RpoN capable of binding the RpoN DNA promoter sequence and inhibiting RpoN-mediated expression in Escherichia coli . We have elucidated a structure-activity relationship for DNA binding by this stapled peptide, improving DNA binding affinity constants in the high nM range. Lead peptides were shown to have low toxicity as determined by their low hemolytic activity at 100 μM and were shown to have anti-virulence activity in a Galleria mellonella model of Pseudomonas aeruginosa infection. These findings support further preclinical development of stapled peptides as antivirulence agents targeting P. aeruginosa .
Keyphrases
- dna binding
- pseudomonas aeruginosa
- transcription factor
- escherichia coli
- circulating tumor
- biofilm formation
- cell free
- single molecule
- cystic fibrosis
- amino acid
- staphylococcus aureus
- acinetobacter baumannii
- nucleic acid
- poor prognosis
- antimicrobial resistance
- signaling pathway
- gene expression
- structure activity relationship
- oxidative stress
- stem cells
- dna methylation
- small molecule
- circulating tumor cells
- drug resistant
- photodynamic therapy
- cancer therapy
- long non coding rna
- genome wide identification
- capillary electrophoresis