Solution structure of a novel <scp>D</scp>‐naphthylalanine substituted peptide with potential antibacterial and antifungal activities

Abstract

Abstract A new type of Trp‐rich peptide, Ac‐KWRRWVRWI‐NH 2 , designated as Pac‐525, was found to possess improved activity against both gram‐positive and negative bacteria. We have synthesized two Pac‐525 analogues, D ‐Pac‐525 containing all D ‐amino acids and D ‐Nal‐Pac‐525, the D ‐Pac‐525 analogue with tryptophan replaced by D ‐β‐naphthylalanine. We have determined the solution structure of D ‐Nal‐Pac‐525 bound to membrane‐mimetic DPC micelles by two‐dimensional NMR methods. The DPC micelle‐bound structure of D ‐Nal‐Pac‐525 adopts a left‐hand α‐helical segment and the positively charged residues are clustered together to form a hydrophilic patch. The surface electrostatic potential map indicates the three D ‐β‐naphthylalanines are packed against the peptide backbone and form an amphipathic structure. A variety of biophysical and biochemical experiments, including circular dichroism, fluorescence spectroscopy, and microcalorimetry, were used to show that D ‐Nal‐Pac‐525 interacted strongly with negatively charged phospholipid vesicles and induced efficient dye release from these vesicles, suggesting that the strong antimicrobial activity of D ‐Nal‐Pac‐525 may be due to interactions with bacterial and fungus membranes. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 738–745, 2007. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com