title: Main-chain length control of conformation, membrane activity, and antibiotic properties of lipopeptaibol sequential analogues.
abstract: To investigate the effect of backbone length and amphiphilicity on the 3D structure, membrane permeability, and antibacterial properties of trichogins, a subclass of lipopeptaibols, we prepared, by the segment condensation approach in solution and chemically characterized, a set of N(alpha)-1-octanoylated -X-(GLUG)(n)-I-L- ( X=G or U where U=Aib; n=1-4) sequential peptide esters. In parallel, the 12-mer (UGGL)(3) aneurism peptide, an analogue of the 11-mer sequential peptide (n=2) with an amino acid insertion was also synthesized and studied. By FT-IR absorption technique, we clearly showed that, in CDCl(3) solution, all peptides essentially populate intramolecularly H-bonded, helical conformations. Moreover, CD spectroscopy indicates that all peptides, with the single exception of the shortest oligomer (the heptamer), adopt mixed 3(10)-/alpha-helical structures, to an extent approximately correlating with main-chain length, in MeOH solution and sodium dodecylsulfate (SDS) micelles. Significant membrane permeability properties were found only for the three longest GLUG-based peptides, with the 15-mer oligomer (n=4) resulting the most active. The lack of activity exhibited by the aneurism peptide in this experiment strongly suggests a relevant role for the sequence amphiphilicity. In addition, antibacterial activity and selectivity were highlighted and demonstrated to be dependent on peptide main-chain length and amphiphilicity, in the sense that the two shortest GLUG-based homologues are active against Gram-positive strains, whereas the two longest homologues are able to penetrate the membranes of the Gram-negative strains, and the UGGL-based aneurism peptide is inactive.
authors.affiliation: Department of Chemistry, University of Padova, Institute of Biomolecular Chemistry, Padova Unit, CNR, I-35131 Padova, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Oancea
authors.forename: Geta
authors.initials: G
authors.lastname: Hilma
authors.forename: Cristina
authors.initials: C
authors.lastname: Peggion
authors.forename: Fernando
authors.initials: F
authors.lastname: Formaggio
authors.forename: Claudio
authors.initials: C
authors.lastname: Toniolo
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002942:Circular Dichroism; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008055:Lipids / Q000737:chemistry*; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D054848:Peptaibols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000900:Anti-Bacterial Agents; D008055:Lipids; D054848:Peptaibols