Spectroscopically labeled peptaibiotics. Synthesis and properties of selected trichogin GA IV analogs bearing a side-chain-monofluorinated aromatic amino acid for (19) F-NMR analysis

Abstract

We prepared by solid-phase methods, chromatographically purified, and characterized three analogs of the ten-amino acid-residue, membrane-active, lipopeptaibiotic trichogin GA IV, each containing a single (4-fluorophenyl)alanine in position 3, 7, or 10, where it replaces the hydrophobic residue Leu(3) , Leu(7) , or Ile(10) , respectively. We incorporated the fluorine probe based on the observation that the (19) F-NMR technique has been extensively utilized to analyze peptidemembrane interactions in biological systems. A detailed conformational investigation in solution, including a membrane-mimetic environment, was performed on these compounds using FT-IR absorption, CD, and 2D-NMR, combined with molecular-dynamics calculations. The experimentally observed, mixed 310 /α-helical structures unequivocally show that the principal conformational features of trichogin GA IV are preserved in all three analogs. Analogies and differences between the behavior of the natural lipopeptaibiotic and those of the peptides characterized by the side-chain monofluorinated aromatic amino acid were found in membrane-permeabilization experiments and antimicrobial assays. The results of a preliminary solution (19) F-NMR study support the view that the (19) F label is an excellent reporter for changes in the helical environment of the peptide.