Boosting Antimicrobial Peptides by Hydrophobic Oligopeptide End Tags

Abstract

A novel approach for boosting antimicrobial peptides through end tagging with hydrophobic oligopeptide stretches is demonstrated. Focusing on two peptides derived from kininogen, GKHKNKGKKNGKHNGWK (GKH17) and HKHGHGH-GKHKNKGKKN (HKH17), tagging resulted in enhanced killing of Gram-positive Staphylococcus aureus, Gram-negative Escherichia coli, and fungal Candida albicans. Microbicidal potency increased with tag length, also in plasma, and was larger for Trp and Phe stretches than for aliphatic ones. The enhanced microbicidal effects correlated to a higher degree of bacterial wall rupture. Analogously, tagging promoted peptide binding to model phospholipid membranes and liposome rupture, particularly for anionic and cholesterol-void membranes. Tagged peptides displayed low toxicity, particularly in the presence of serum, and resisted degradation by human leukocyte elastase and by staphylococcal aureolysin and V8 proteinase. The biological relevance of these findings was demonstrated ex vivo and in vivo in porcine S. aureus skin infection models. The generality of end tagging for facile boosting of antimicrobial peptides without the need for post-synthesis modification was also demonstrated.

Structure-Activity Relationship of Synthetic Variants of the Milk-Derived Antimicrobial Peptide α s2 -Casein f(183–207)

“…End tagging by hydrophobic amino acid stretches allows the primary AMP sequence to be retained at the same time as efficient but selective membrane anchoring is achieved. Although a number of hydrophobic amino acids may be used as end tags, Trp and Phe end tags have emerged as particularly potent choices (30). Through interaction with the phospholipid membrane, Trp/Phe residues are able to insert into the membrane, acting as an anchor for the peptide and resulting in increased bactericidal effects (31,32).…”

Structure-Activity Studies and Therapeutic Potential of Host Defense Peptides of Human Thrombin

“…Considering this property of AMPs, various strategies have been employed in order to optimize the therapeutic index, including the use of combinational library approaches (1), stereoisomers composed of Damino acids (40) or cyclic D,L-␣-peptides (8), and quantitative structure-activity relationship (QSAR) and high-throughputbased screening assays (9,15,18,35,44). Furthermore, a novel approach for boosting AMPs through end-tagging with hydrophobic oligopeptide stretches has recently been demonstrated (23,32,33,41). The peptides were active ex vivo and in vivo in porcine S. aureus skin infection models and in P. aeruginosainfected wound models (23,32,33,41).…”

Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

“…[19][20][21] Hence, terminal modifications could be a useful strategy for enhancing AMP and ACP's stability against proteolytic degradation. However, the influence of terminal modifications on the anticancer activity and cell selectivity of ACPs…”