Short KR-12 analogs designed from human cathelicidin LL-37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity
Short KR-12 analogs designed from human cathelicidin LL-37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity
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DOI：
10.1002/psc.2552
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发表时间：
2013-11-01
影响因子：
2.1
通讯作者：
Shin, Song Yub
中科院分区：
文献类型：
--
作者：
Jacob, Binu;Park, Il-Seon;Shin, Song Yub
KR-12 （LL-37的18-29残基）是LL-37中最小的具有抗菌活性的肽。为了优化具有抗菌和抗内毒素活性且不具有哺乳动物细胞毒性的α -螺旋抗菌短肽，我们设计并合成了一系列的KR-12类似物。疏水性最高的类似物KR-12-a5和KR-12-a6对脂多糖（LPS）刺激的肿瘤坏死因子- α产生有更大的抑制作用，并且具有更高的脂多糖结合活性。我们已经观察到抗菌活性与电荷无关，但LPS中和需要疏水性和净正电荷的平衡。在KR-12类似物中，与亲本LL-37相比，KR-12-a2、KR-12-a3和KR-12-a4对红细胞上的细菌表现出更高的细胞特异性，并保留了抗内毒素活性。与LL-37相比，KR-12-a5表现出最强的抗内毒活性，但细胞特异性基本相同。此外，这些KR-12类似物（KR-12-a2, KR-12-a3， KR-12-a4和KR-12-a5）对耐甲氧西林金黄色葡萄球菌表现出有效的抗菌活性（最小抑制浓度为4 μ M）。综上所述，这些KR-12类似物具有作为新型抗菌和抗炎治疗剂的未来发展潜力。版权所有(C) 2013欧洲多肽协会和约翰威利& Sons有限公司
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.