Disruption of the β-Sheet Structure of Cyclic Peptides by Single Amino Acid Substitution: Influence on Prokaryotic and Eukaryotic Cell Viability

We have studied the effect of ring size on cyclic β-sheet peptides and showed that we were able to dissociate antimicrobial activity from hemolytic activity [1]. The 14-residue peptide, GS 14, displayed weak antimicrobial activity and strong hemolytic activity. In a subsequent study of GS 14 analogs, we reversed this profile to create peptides with strong antimicrobial activity and weak hemolytic activity. Single amino acids within the GS 14 sequence were substituted with their corresponding D- or L-enantiomers at all 14 ring positions. These analogs had reduced amphipathicity and disrupted β-sheet structure when compared to GS 14 (represented in Figure 1, left) [2,3]. Of these analogs, the D-Lys substitution at position 4 (Figure 1, right) yielded the largest increase in therapeutic index (lytic specificity for prokaryotic vs eukaryotic cells) [3]. Here, we substitute other amino acids (both D- and L-enantiomers) at position 4 and study their influence on hemolytic and antimicrobial activity.