Design of a potent antibiotic peptide based on the active region of human defensin 5.
Design of a potent antibiotic peptide based on the active region of human defensin 5.
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DOI：
10.1021/jm501824a
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发表时间：
2015-03
影响因子：
7.3
通讯作者：
Cheng Wang;M. Shen;N. Gohain;W. Tolbert;Fang Chen;Naixin Zhang;Ke Yang;Aiping Wang;Yong-ping Su;T. Cheng;Jinghong Zhao;M. Pazgier;Junping Wang
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文献类型：
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作者：
Cheng Wang;M. Shen;N. Gohain;W. Tolbert;Fang Chen;Naixin Zhang;Ke Yang;Aiping Wang;Yong-ping Su;T. Cheng;Jinghong Zhao;M. Pazgier;Junping Wang
人类防御素 5 (HD5) 是一种具有 C 末端活性区域的广谱抗菌肽。为了促进这种肽开发成抗生素，我们最初用 Arg 取代 Glu21，因为它是位于活性区域周围的电负性残基。尽管不利于二聚体形成，但 E21R 取代显着增强了 HD5 的抗菌活性并增加了其穿透细胞膜的能力，这表明增加正电荷可以补偿二聚体破坏的影响。随后进行部分Arg扫描诱变，选择Thr7替换为Arg，进一步增强抗菌活性。新设计的肽 T7E21R-HD5 即使在盐水和血清溶液中也表现出有效的抗菌活性。与单体E21R-HD5相比，T7E21R-HD5组装成具有平行β链的非典型二聚体，从而扩大了增加正电荷在杀菌活性中的作用，并为进一步的防御素衍生抗生素设计提供了有用的指导。
Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C-terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensated for the effect of dimer disruption. Subsequently, a partial Arg scanning mutagenesis was performed, and Thr7 was selected for replacement with Arg to further strengthen the antibacterial activity. The newly designed peptide, T7E21R-HD5, exhibited potent antibacterial activity, even in saline and serum solutions. In contrast to monomeric E21R-HD5, T7E21R-HD5 assembled into an atypical dimer with parallel β strands, thus expanding the role of increasing electropositive charge in bactericidal activity and providing a useful guide for further defensin-derived antibiotic design.