Spectroscopic and structural approach to search smallest active analogue of an antimicrobial peptide from frog

Recently, antimicrobial peptides have become a potential source of new antibiotics to combat the increasing emergence of drug-resistant bacteria. Several antimicrobial peptides such as magainin, a 23-residue antimicrobial peptide, have been successful in pharmaceutical and commercial development. Six kinds of peptides, named gaegurins (GGNs), 24˜37 residue peptide, have been isolated from the Asian frog Rana rugosa. Gaegurin 5 is a 24-residue, membrane-active antimicrobial peptide. We recently reported the antimicrobial activities of two novel undecapeptides derived from an inactive N-terminal fragment (residues 1 to 11) of gaegurin 5 [1]. The anticancer activities of the two antimicrobial undecapeptide analogues were additionally identified [2]. The relationships between their structural properties and biological activities were assessed by characterizing the fundamental structural determinant for the basic membrane interaction. The circular dichroism and nuclear magnetic resonance results revealed that in a membrane-mimetic environment, the active peptides adopt a more stabilized helical conformation than that of the inactive fragment, and this conformation conferred an overall amphipathicity to the active peptides. Therefore, the most decisive factor responsible for the activity and selectivity could be the intramolecular amphipathic cooperativity, rather than the amphipathicity itself. Especially, the tryptophan residue of the active peptides seems to play a crucial role at the critical amphipathic interface that promotes and balances the amphipathic cooperativity, by stabilizing both the hydrophilic and hydrophobic interactions with the membrane.

References: 1. Won, H.S. et al. (2004)J. Biol. Chem. 279:14784–14791. 2. Won, H.S. et al. (2006)J. Med. Chem. 49: 4886–4895.