Design and synthesis of novel antimicrobial peptide scaffolds

Abstract

Muramic acid (Mur), a sugar amino acid (SAA), is present in the cell walls of bacteria asN-acetyl muramic acid (MurNAc) where together with ofN-acetylglucosamine (GlcNAc) and peptide makes main building block of peptidoglycan (PGN). It was challenging to incorporate muramic acid as SAA characteristic for bacteria into the peptides and investigate the antimicrobial activity of these scaffolds. Four building units were used in designing the desired peptide: muramic acid, tetrapeptide Leu-Ser-Lys-Leu, N^ε-Lys, and Asn. Positions of three components were changeable while the position of Asn was always C-terminal (in linear peptides). The glycopeptide libraries of linear and cyclic peptides were synthesized using solid-phase peptide synthesis (SPPS). The antimicrobial effect of linear and cyclic glycopeptides, as well as the LSKL sequence used as a control, was investigated on several standard laboratory microbial strains. Liner glycopeptide with sequences Leu-Ser-Lys-Leu-N^ε-Lys-Mur-Asn was active onStaphylococcus aureus(Gram-positive bacteria). Prepared compounds did not show activity towards applied tumor and normal human cell lines.

Keywords: Antimicrobial peptides; Muramic acid (Mur); Peptide library; Solid-phase peptide synthesis; Sugar amino acid (SAA).