Amphiphilic Cationic β^3R3-Peptides: Membrane Active Peptidomimetics and Their Potential as Antimicrobial Agents

Abstract

We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β(3R3)-peptides, and evaluate their potential as antimicrobial agents. The design criteria, the building block and oligomer synthesis as well as a detailed structure-activity relationship (SAR) study are reported. Specifically, infrared reflection absorption spectroscopy (IRRAS) was employed to investigate structural features of amphiphilic cationic β(3R3)-peptide sequences at the hydrophobic/hydrophilic air/liquid interface. Furthermore, Langmuir monolayers of anionic and zwitterionic phospholipids have been used to model the interactions of amphiphilic cationic β(3R3)-peptides with prokaryotic and eukaryotic cellular membranes in order to predict their membrane selectivity and elucidate their mechanism of action. Lastly, antimicrobial activity was tested against Gram-positive M. luteus and S. aureus as well as against Gram-negative E. coli and P. aeruginosa bacteria along with testing hemolytic activity and cytotoxicity. We found that amphiphilic cationic β(3R3)-peptide sequences combine high and selective antimicrobial activity with exceptionally low cytotoxicity in comparison to values reported in the literature. Overall, this study provides further insights into the SAR of antimicrobial peptides and peptidomimetics and indicates that amphiphilic cationic β(3R3)-peptides are strong candidates for further development as antimicrobial agents with high therapeutic index.

Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

“…This intermediate was coupled with leucine-derived amino azide 5 28 and separately, the novel arginine-derived amino azide 14 (Scheme 2b) to give terminal azides 6 and 15, respectively, in near quantitative yields. Excess amine (1.5−2.0 equiv) was necessary during these reactions to avoid competitive consumption of 4 via intramolecular attack of its protected guanidine on the activated acid, which occurred as a side reaction under stoichiometric conditions.…”

Photo-cleavable purification/protection handle assisted synthesis of giant modified proteins with tandem repeats

“…The synthesis of 4 started from the tert -butyl deprotection of compound 1 ,58 followed by acyl chlorination and coupling with amine 2 59 to afford compound 3 (36% yield over 3 steps). Benzyl bromide 3 reacted with the thiol group of cysteine, and this was followed by Boc protection of the α-amine to yield building block 4 (64% yield over 2 steps) (Fig.…”

Peptides and Dendrimers: How to Combat Viral and Bacterial Infections

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