title: Enhancement of the anti-inflammatory activity of temporin-1Tl-derived antimicrobial peptides by tryptophan, arginine and lysine substitutions.
abstract: Temporin-1Tl (TL) is a 13-residue frog antimicrobial peptide (AMP) exhibiting potent antimicrobial and anti-inflammatory activity. To develop novel AMP with improved anti-inflammatory activity and antimicrobial selectivity, we designed and synthesized a series of TL analogs by substituting Trp, Arg and Lys at selected positions. Except for Escherichia coli and Staphylococcus epidermidis, all TL analogs exhibited retained or increased antimicrobial activity against seven bacterial strains including three methicillin-resistant Staphylococcus aureus strains compared with TL. TL-1 and TL-4 showed a little increase in antimicrobial selectivity, while TL-2 and TL-3 displayed slightly decreased antimicrobial selectivity because of their about twofold increased hemolytic activity. All TL analogs demonstrated greatly increased anti-inflammatory activity, evident by their higher inhibition of the production tumor necrosis factor-α (TNF-α) and nitric oxide and the mRNA expression of inducible nitric oxide synthase and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells, compared with TL. Taken together, the peptide anti-inflammatory activity is as follows: TL-2 ≈ TL-3 ≈ TL-4 > TL-1 > TL. In addition, LPS binding ability of the peptides corresponded with their anti-inflammatory activity. These results apparently suggest that the anti-inflammatory activity of TL analogs is associated with the direct binding ability between these peptides and LPS. Collectively, our designed TL analogs possess improved anti-inflammatory activity and retain antimicrobial activity without a significant increase in hemolysis. Therefore, it is evident that our TL analogs constitute promising candidates for the development of peptide therapeutics for gram-negative bacterial infection.
authors: Department of Medical Science, Graduate School, Chosun University, Gwangju, 501-759, Korea.
authors: Ganesan
authors: G
authors: Rajasekaran
authors: Department of Pharmacology, School of Medicine, Chosun University, Gwangju, 501-759, Korea.
authors: Radhakrishnan
authors: R
authors: Kamalakannan
authors: Department of Medical Science, Graduate School, Chosun University, Gwangju, 501-759, Korea.|Department of Cellular and Molecular Medicine, School of Medicine, Chosun University, Gwangju, 501-759, Korea.
authors: Song Yub
authors: SY
authors: Shin
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry*; D002460:Cell Line; D008070:Lipopolysaccharides / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D011506:Proteins / Q000737:chemistry*; D014364:Tryptophan / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; D008070:Lipopolysaccharides; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C104501:temporin; D014364:Tryptophan; D001120:Arginine; D008239:Lysine
keywords: anti-inflammatory activity; antimicrobial activity; gram-negative infection; temporin-1T1; temporin-1T1 analogs