Short KR-12 analogs designed from human cathelicidin LL-37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity

被引:89
作者
Jacob, Binu [1 ]
Park, Il-Seon [1 ,2 ]
Bang, Jeong-Kyu [3 ]
Shin, Song Yub [1 ,2 ]
机构
[1] Chosun Univ, Sch Med, Dept Biomat, Kwangju 501759, South Korea
[2] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea
[3] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chungbuk, South Korea
关键词
human cathelicidin LL-37; KR-12; analogs; antimicrobial activity; antiendotoxic activity; HOST-DEFENSE PEPTIDES; LIPOPOLYSACCHARIDE NEUTRALIZATION; STRUCTURAL-CHARACTERIZATION; ANTIBACTERIAL; BINDING; ALPHA; CAP18; LPS; TRYPTOPHAN;
D O I
10.1002/psc.2552
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
KR-12 (residues 18-29 of LL-37) was known to be the smallest peptide of human cathelicidin LL-37 possessing antimicrobial activity. In order to optimize alpha-helical short antimicrobial peptides having both antimicrobial and antiendotoxic activities without mammalian cell toxicity, we designed and synthesized a series of KR-12 analogs. Highest hydrophobic analogs KR-12-a5 and KR-12-a6 displayed greater inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha production and higher LPS-binding activity. We have observed that antimicrobial activity is independent of charge, but LPS neutralization requires a balance of hydrophobicity and net positive charge. Among KR-12 analogs, KR-12-a2, KR-12-a3 and KR-12-a4 showed much higher cell specificity for bacteria over erythrocytes and retained antiendotoxic activity, relative to parental LL-37. KR-12-a5 displayed the strongest antiendotoxic activity but almost similar cell specificity as compared with LL-37. Also, these KR-12 analogs (KR-12-a2, KR-12-a3, KR-12-a4 and KR-12-a5) exhibited potent antimicrobial activity (minimal inhibitory concentration: 4 mu M) against methicillin-resistant Staphylococcus aureus. Taken together, these KR-12 analogs have the potential for future development as a novel class of antimicrobial and anti-inflammatory therapeutic agents. Copyright (C) 2013 European Peptide Society and John Wiley & Sons, Ltd.
引用
收藏
页码:700 / 707
页数:8
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