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-positive bacteria S. aureus , S. albus and Gram-negative 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 s table α-helix domain conformation which is similar to Loloatin C in membrane mimetic solution. All the tested peptides demonstrate low hemolytic toxicity to rabbit red blood cells with EC 50 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 production. The discussion of structure-activity relationship is also included
Highlights
During the last few decades, the problem of bacterial resistance to antibiotics becomes a major issue in human health and the construction of new therapeutic agents to combat micro-organisms resistant to traditional antibiotics is nowaday an urgent task [13]
Several cyclodecapeptides including Gramicidin S [7], Tyrocidine A [8], and Loloatin C [9,10,11,12] (Figure 1), belonging to antimicrobial peptides (AMPs), have received a great deal of attentions due to their highly desirable mechanism targeting on the bacterial membrane, which the bacteria are hard to develop resistance toward them [4]
Despite all the potential advantages over conventional antibiotics mentioned above, pharmaceutical development of these cyclopeptides into therapeutic agents has been limited by the large size of these peptides, the corresponding high production cost to synthesize in bulk, and cytotoxicity to red blood cells
Summary
During the last few decades, the problem of bacterial resistance to antibiotics becomes a major issue in human health and the construction of new therapeutic agents to combat micro-organisms resistant to traditional antibiotics is nowaday an urgent task [13]. Despite all the potential advantages over conventional antibiotics mentioned above, pharmaceutical development of these cyclopeptides into therapeutic agents has been limited by the large size of these peptides, the corresponding high production cost to synthesize in bulk, and cytotoxicity to red blood cells. To address these issues, perhaps one effective pathway is to simplify the complex cyclopeptide into small linear peptide based on the pharmacophore. Through narrowing Loloatin C into three cyclic hexapeptides and comparing their antimicrobial properties, it was deduced that the sequence -D-Tyr-Pro-Trp-D-Phe- was essential to its antimicrobial activities, and might be the pharmacophore of Loloatin C [16].
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