Abstract
Carbohydrates are considered as promising templates for the display of multiple copies of antimicrobial peptides. Herein, we describe the design and synthesis of chimeric structures containing two or four copies of the antimicrobial peptides KKLFKKILKYL-NH2 (BP100) and KKLfKKILKYL-NH2 (BP143) attached to the carbohydrate template cyclodithioerythritol (cDTE) or α-D-galactopyranoside (Galp). The synthesis involved the preparation of the corresponding peptide aldehyde followed by coupling to an aminooxy-functionalized carbohydrate template. After purification, the multivalent display systems were obtained in high purities (90–98%) and in good yields (42–64%). These compounds were tested against plant and human pathogenic bacteria and screened for their cytotoxicity on eukaryotic cells. They showed lower MIC values than the parent peptides against the bacteria analyzed. In particular, the carbopeptides derived from cDTE and Galp, which contained two or four copies of BP100, respectively, were 2- to 8-fold more active than the monomeric peptide against the phytopathogenic bacteria. These results suggest that preassembling antimicrobial peptides to multimeric structures is not always associated with a significant improvement of the activity. In contrast, the carbopeptides synthesized were active against human red blood cells pointing out that peptide preassembly is critical for the hemolytic activity. Notably, peptide preassembly resulted in an enhanced bactericidal effect.
Highlights
The emergence of antibiotic resistance is a major problem in human health as well as in agronomy and there is a considerable current interest in developing novel antimicrobial compounds [1,2]
The sequence of the peptide aldehydes was based on the peptides KKLFKKILKYL-NH2 (BP100) and KKLfKKILKYL-NH2 (BP143), which have been shown to display high antibacterial activity [28,29]
In this study we used carbohydrate templates for the design of multivalent antimicrobial peptides targeted to control plant and human pathogenic bacteria and explored whether multivalency enhances the antimicrobial activity. These multivalent constructs were obtained by preassembling the antimicrobial peptides BP100 and BP143 to a cDTE or a Galp carbohydrate template through oxime formation
Summary
The emergence of antibiotic resistance is a major problem in human health as well as in agronomy and there is a considerable current interest in developing novel antimicrobial compounds [1,2]. Cleavage of the peptidyl resins with TFA/H2O (95:5) followed by purification by reversed-phase high-performance liquid chromatography (RP-HPLC) afforded peptide aldehydes 4 and 5 in 99% purity, and their structure was confirmed by electrosprayionization mass spectrometry (ESIMS). The synthesis of carbopeptide 1 was achieved by oxime ligation of cDTE, previously lyophilized, with peptide aldehyde 4 in a 1:1 solution of CH3CN and acetate buffer (0.1 M, pH 4.76) containing aniline (100 mM) at room temperature for 3 h.
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