title: Solution synthesis, conformational analysis, and antimicrobial activity of three alamethicin F50/5 analogs bearing a trifluoroacetyl label.
abstract: We prepared, by solution-phase methods, and fully characterized three analogs of the membrane-active peptaibiotic alamethicin F50/5, bearing a single trifluoroacetyl (Tfa) label at the N-terminus, at position 9 (central region) or at position 19 (C-terminus), and with the three Gln at positions 7, 18, and 19 replaced by Glu(OMe) residues. To add the Tfa label at position 9 or 19, a γ-trifluoroacetylated α,γ-diaminobutyric acid (Dab) residue was incorporated as a replacement for the original Val(9) or Glu(OMe)(19) amino acid. We performed a detailed conformational analysis of the three analogs (using FT-IR absorption, CD, 2D-NMR, and X-ray diffraction), which clearly showed that Tfa labeling does not introduce any dramatic backbone modification in the predominantly α-helical structure of the parent peptaibiotic. The results of an initial solid-state (19)F-NMR study on one of the analogs favor the conclusion that the Tfa group is a very promising reporter for the analysis of peptaibioticmembrane interactions. Finally, we found that the antimicrobial activities of the three newly synthesized analogs depend on the position of the Tfa label in the peptide sequence.
authors.affiliation: ICB, Padova Unit, CNR, Department of Chemistry, University of Padova, I-35131 Padova. marta.dezotti@unipd.it.
authors.forename: Marta
authors.initials: M
authors.lastname: De Zotti
authors.forename: Gema
authors.initials: G
authors.lastname: Ballano
authors.forename: Micha
authors.initials: M
authors.lastname: Jost
authors.forename: Evgeniy S
authors.initials: ES
authors.lastname: Salnikov
authors.forename: Burkhard
authors.initials: B
authors.lastname: Bechinger
authors.forename: Simona
authors.initials: S
authors.lastname: Oancea
authors.forename: Marco
authors.initials: M
authors.lastname: Crisma
authors.forename: Claudio
authors.initials: C
authors.lastname: Toniolo
authors.forename: Fernando
authors.initials: F
authors.lastname: Formaggio
mesh_terms: D000408:Alamethicin / Q000031:analogs & derivatives* / Q000737:chemistry; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D002942:Circular Dichroism; D004353:Drug Evaluation, Preclinical; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000890:Anti-Infective Agents; D000408:Alamethicin
keywords: Alamethicin analogs; Antimicrobial activity; Conformational analysis; Fluorinated labels; Molecular dynamics; NMR Spectroscopy