Structure-function relationship of king cobra cathelicidin
Structure-function relationship of king cobra cathelicidin
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眼镜王蛇抗菌素的结构-功能关系
DOI：
10.1016/j.peptides.2010.05.005
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发表时间：
2010-08-01
期刊：
影响因子：
3
通讯作者：
Zhang, Yun
中科院分区：
文献类型：
--
作者：
Zhang, Yong;Zhao, Hui;Zhang, Yun
眼镜王蛇抗菌肽（OH-CATH）由34个氨基酸组成，具有很强的抗菌活性和很弱的溶血活性。OH-CATH可以作为开发新型治疗药物的有价值的模板。本研究合成了OH-CATH及其六个类似物，并根据它们的杀菌和溶血活性探讨了它们的结构与功能关系。OH-CATH（3-34）和OH-CATH（5-34）的实验结果表明，OH-CATH的N端4个氨基酸残基对溶血活性起重要作用，但对杀菌活性影响不大。在OH-CATH及其类似物中，OH-CATH（5-34）具有最低的溶血活性，同时保持了强的抗菌活性。为了评价其潜在的用途，将OH-CATH（5-34）的生物活性与pexiganan的生物活性进行比较。OH-CATH（5-34）对5种不同物种（11种实验室菌株）的杀菌活性比pexiganan（4-16 μ g/ml vs 8-32 μ g/ml）强2-4倍。在200 μ g/ml剂量下，OH-CATH（5-34）对人红细胞的溶血活性为0.69%，而Pexiganan的溶血活性为16.5%。OH-CATH（5-34）对原代兔心室内皮细胞和四种人癌细胞系显示出非常弱的细胞毒活性，而pexiganan对这五种细胞系显示出强的细胞毒活性（IC 50 =20-90 μ g/ml）。OH-CATH（5-34）对小鼠的静脉注射LD 50值比Pexiganan（175 mg/kg vs 25 mg/kg）高7倍。综上所述，我们的结果表明，OH-CATH（5-34）应被视为开发治疗药物的优秀候选者。(C)2010年爱思唯尔公司All rights reserved.
King cobra cathelicidin (OH-CATH) is composed of 34 amino acid residues having strong antibacterial and very weak hemolytic activities as reported by us recently. OH-CATH can be served as a valuable template to develop novel therapeutic drugs. In this study, OH-CATH and six of its analogs were synthesized to explore their structure-function relationships based on their bactericidal and hemolytic activities. Experimental results of OH-CATH(3-34) and OH-CATH(5-34) indicated that the N-terminal 4 amino acid residues of OH-CATH played an important role on its hemolytic activity but had weak effects on its bactericidal activity. Among OH-CATH and its analogs, OH-CATH(5-34) had the lowest hemolytic activity while maintained strong antimicrobial activity. To evaluate its potential usage, the biological activities of OH-CATH(5-34) were compared with those of pexiganan. The bactericidal activity of OH-CATH(5-34) against 5 different species (11 laboratory strains) was 2-4 times stronger than that of pexiganan (4-16 mu g/ml vs 8-32 mu g/ml). Hemolytic activity of OH-CATH(5-34) against human erythrocytes was 0.69% while that of pexiganan was 16.5% at the dosage of 200 mu g/ml. OH-CATH(5-34) showed very weak cytotoxic activities against primary rabbit ventricular endothelial cells and four human cancer cell lines whereas pexiganan showed strong cytotoxic activity against these five cell lines (IC50=20-90 mu g/ml). The intravenous LD50 value of OH-CATH(5-34) on mice was 7-fold higher than that of pexiganan (175 mg/kg vs 25 mg/kg). Taken together, our results suggested that OH-CATH(5-34) should be considered as an excellent candidate for developing therapeutic drugs. (C) 2010 Elsevier Inc. All rights reserved.