Short Simple Linear Peptides Mimic Antimicrobial Complex Cyclodecapeptides Based on the Putative Pharmacophore

Abstract

The sequence, -d-Tyr-Pro-Trp-d-Phe- has been identified from Loloatin C as a promising pharmacophore model for developing new antimicrobial peptides. Most of the linear peptides designed based on this sequence exhibits strong antimicrobial activities against Gram-pos. bacteria S. aureus, S. albus and Gram-neg. bacteria E. coli strains with MIC values ranging from 15.6 to 62.5 μg/mL, although they are inactive against fungus C. albicans, multi-drug resistant bacterial MRSA and K. pneumoniae. The linear hexapeptide, H-Asp-d-Tyr-Pro-Trp-d-Phe-Asn-OH (L1) is confirmed the most active peptide among them. L1 possesses stable α-helix domain conformation which is similar to Loloatin C in membrane mimetic soln. All the tested peptides demonstrate low hemolytic toxicity to rabbit red blood cells with EC50 values higher than 120 μg/mL and low cytotoxicity to mouse fibroblast cells. The successful simplication of Loloatin C to a short linear peptide simplifies the synthetic process and lowers costs of prodn. The discussion of structure-activity relationship is also included. [on SciFinder(R)]