Design of Short Indolicidin Analogs with Enhanced Prokaryotic Selectivity
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Indolicidin (ID) is a 13-residue Trp-rich antimicrobial peptide (AMP) isolated from bovine neutrophils. In addition to having a high antimicrobial potency, it is also toxic to mammalian cells. To develop novel ID-derived AMPs with shorter lengths and enhanced prokaryotic selectivities (meaning potent antimicrobial activity against bacterial cells without toxicity against mammalian cells) over the parental ID, several ID analogs were designed and synthesized. Finally, 10-residue ID analogs (SI, SI-PA, SI-WF and SI-WL) with much higher prokaryotic selectivity than the parental ID were developed. Our results suggest that the hydrophobic and aromatic amino acids at the central position of the analog SI with the highest prokaryotic selectivity are important for potent antimicrobial activity, but two Pro residues do not affect antimicrobial activity. The order of prokaryotic selectivity for ID and its designed analogs was SI > SI-PA > SI-WF > SI-WL > ID > SI-WA. Taken together, our designed short ID analogs could be developed as therapeutic agents for treating bacterial infections.
Abstract
Indolicidin (ID) is a 13-residue Trp-rich antimicrobial peptide (AMP) isolated from bovine neutrophils. In addition to having a high antimicrobial potency, it is also toxic to mammalian cells. To develop novel ID-derived AMPs with shorter lengths and enhanced prokaryotic selectivities (meaning potent antimicrobial activity against bacterial cells without toxicity against mammalian cells) over the parental ID, several ID analogs were designed and synthesized. Finally, 10-residue ID analogs (SI, SI-PA, SI-WF and SI-WL) with much higher prokaryotic selectivity than the parental ID were developed. Our results suggest that the hydrophobic and aromatic amino acids at the central position of the analog SI with the highest prokaryotic selectivity are important for potent antimicrobial activity, but two Pro residues do not affect antimicrobial activity. The order of prokaryotic selectivity for ID and its designed analogs was SI > SI-PA > SI-WF > SI-WL > ID > SI-WA. Taken together, our designed short ID analogs could be developed as therapeutic agents for treating bacterial infections.
참고문헌 (15)
- Ando, S., "Structure-activity relationship of indolicidin, a Trp-rich antibacterial peptide", J. Pept. Sci, 16, pp.171~177 (2010)
- Andreu, D, "Animal antimicrobial peptides: an overview", Biopolymers, 47, pp.415~433 (1988)
- Chen, Y, "Rational design of α-helical antimicrobial peptides with enhanced activities and specificity", therapeutic index, 2005, pp.280, 12316~12329
- Fazio, M. A, "Biological and structural characterization of new linear gomesin analogues with improved therapeutic indices", Biopolymers, 88, pp.386~400 (2007)
- Friedrich, C. L, "Structure and mechanism of action of an indolicidin peptide derivative with improved activity against gram-positive bacteria", J. Biol. Chem, 276, pp.24015~24022 (2001)
- Hsu, C. H, "Structural and DNAbinding studies on the bovine antimicrobial peptide, indolicidin: evidence for multiple conformations involved in binding to membranes and DNA", Nucleic Acids Res, 33, pp.4053~4064 (2005)
- Merrifield, B., "Concept and early development of solidphase peptide synthesis", Methods Enzymol, 289, pp.3~13 (1997)
- 신송엽, "Design of novel indolicidin-derived antimicrobial peptides with enhanced cell specificity and potent anti-inflammatory activity", PEPTIDES, 30, pp.832~838, ELSEVIER SCIENCE INC
- Nan, Y. H, "Investigating the effects of positive charge and hydrophobicity on the cell selectivity, mechanism of action and anti-inflammatory activity of a Trp-rich antimicrobial peptide indolicidin", FEMS Microbiol. Lett, 292, pp.134~140 (2009)
- Rozek. A, "Structure of the bovine antimicrobial peptide indolicidin bound to dodecylphosphocholine and sodium dodecyl sulfate micelles", Biochemistry, 39, pp.15765~15774 (2000)
- Rozek, A, "Structure-based design of an indolicidin peptide analogue with increased protease stability", Biochemistry, 42, pp.14130~14138 (2003)
- Ryge, T. S, "New indolicidin analogues with potent antibacterial activity", J. Pept. Res, 64, pp.171~185 (2004)
- Selsted, M. E, "Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils", J. Biol. Chem, 267, pp.4292~4295 (1992)
- Zasloff, M, "Antimicrobial peptides of multicellular organisms", Nature, 415, pp.389~395 (2002)
- Zhu, W. L, "Substitution of the leucine zipper sequence in melittin with peptoid residues affects self-association, cell selectivity, and mode of action", Biochim. Biophys. Acta, 1768, pp.1506~1517 (2007)