Tuning the Activity of a Short Arg-Trp Antimicrobial Peptide by Lipidation of a C- or N-Terminal Lysine Side-Chain

Abstract

The attachment of lipids to C-or N-terminally positioned lysine side-chain amino groups increases the activity of a short synthetic (Arg-Trp) 3 antimicrobial peptide significantly, making these peptides even active against pathogenic Gram-negative bacteria. Thus, a peptide with strong activity against S. aureus (1.1−2 μM) and good activity against A. baumannii and P. aeruginosa (9−18 μM) was identified. The most promising peptide causes 50% hemolysis at 285 μM and shows some selectivity against human cancer cell lines. Interestingly, the increased activity of ferrocenoylated peptides is mostly due to the lipophilicity of the organometallic fragment.

Synthesis and antibacterial activity of trivalent ultrashort Arg-Trp-based antimicrobial peptides (AMPs)

“…10 This value represents the lowest concentration of compound that is needed to inhibit growth of the bacteria. 29 For this, two Gram-negative and three Gram-positive bacterial strains were used (Table 1).…”

Small cationic antimicrobial peptides delocalize peripheral membrane proteins

“…It is effective against Grampositive bacteria including methicillin-resistant Staphylococcus aureus strains, is moderately effective against Gram-negative bacteria, has low toxicity against human cell lines, and displays low hemolytic activity (18). MP196 therefore is a promising lead structure for derivatization and already has yielded peptides with improved activities and altered pharmacological properties (19). For example, in a recent systematic L-to-D exchange scan peptides with significantly reduced hemolytic activity could be identified (20).…”

Exploring Structure–Activity Relationships in Synthetic Antimicrobial Peptides (synAMPs) by a Ferrocene Scan

“…Such metal derivatization has been achieved by onresin N-terminal acetylation [9] or on-resin acetylation of the side-chain of lysine. [10] Enhanced activities against various bacterial strains were achieved and, moreover, the mode of action of this type of organometallic antimicrobial peptide has recently been described, [11] which makes them very interesting for further antibiotic development. Many examples of the structure-activity relationship (SAR) of peptides have been published, which has allowed certain residues to be identified as being crucial for activity, and these should clearly not be modified or removed.…”

“…To avoid an undesired disruption of the alternating hydrophilic/hydrophobic side-chain motif by the incorporation of this amino acid into the (RW) 3 sequence, we decided to use the ferrocene amino acid as a tryptophan substitute, because it was expected that the bulky, hydrophobic ferrocene moiety will behave similarly to tryptophan. [10] A few ferrocene-based amino acids are known with ferrocene either in the peptide backbone [13] or in the side-chain, [14] for example, ferrocenoylalanine. However, no Fmoc-protected amino acids have been reported so far that would be suitable for standard Fmoc/tBu solid-phase peptide synthesis (SPPS).…”