title: Effects of Aib residues insertion on the structural-functional properties of the frog skin-derived peptide esculentin-1a(1-21)NH2.
abstract: Antimicrobial peptides (AMPs) play a key role in the defence mechanism of living organisms against microbial pathogens, displaying both bactericidal and immunomodulatory properties. They are considered as a promising alternative to the conventional antibiotics towards which bacteria are becoming highly resistant. Recently, a derivative of the frog skin AMP esculentin-1a, esculentin-1a(1-21)NH2[Esc(1-21)], showed a strong and fast membranolytic activity against Gram-negative bacteria but with a lower efficacy against Gram-positive ones. Here, with the aim to increase the α-helicity of Esc(1-21) and the expected potency against Gram-positive bacteria, we designed an analog bearing three α-aminoisobutyric acid (Aib) residues at positions 1, 10, and 18 of its primary structure. We demonstrated that the incorporation of Aib residues: (1) promoted the α-helix conformation of Esc(1-21), as confirmed by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopies; (2) was sufficient to make this analog more active than the parent peptide against several Gram-positive bacterial strains without affecting its activity against Gram-negative bacteria; and (3) resulted to be devoid of toxic effect toward epithelial cells at the active antimicrobial concentrations. These results suggest that replacement of L-amino acids with Aib residues has beneficial effects on the structure and properties of the membrane-active peptide Esc(1-21), making it a better candidate for the design and development of selective drugs against Gram-positive bacteria.
authors.affiliation: Institute of Biomolecular Chemistry, Padova Unit, CNR, Via Marzolo 1, 35131, Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Biondi
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Via degli Apuli, 9, 00185, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Casciaro
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Via degli Apuli, 9, 00185, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Grazia
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Via degli Apuli, 9, 00185, Rome, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Cappiello
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Via degli Apuli, 9, 00185, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Luca
authors.affiliation: Institute of Biomolecular Chemistry, Padova Unit, CNR, Via Marzolo 1, 35131, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Crisma
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Via degli Apuli, 9, 00185, Rome, Italy. marialuisa.mangoni@uniroma1.it.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Mangoni
mesh_terms: D000072283:A549 Cells; D000595:Amino Acid Sequence; D000621:Aminoisobutyric Acids / Q000737:chemistry*; D029845:Amphibian Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D015202:Protein Engineering; D011898:Ranidae / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000621:Aminoisobutyric Acids; D029845:Amphibian Proteins; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C092874:esculentin protein, Rana esculenta; C100049:2-aminoisobutyric acid
keywords: Antimicrobial peptides; Gram-positive bacteria; NMR; α-Aminoisobutyric acid