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Enhanced cell selectivity of hybrid peptides with potential antimicrobial activity and immunomodulatory effect.
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2020-01-15 , DOI: 10.1016/j.bbagen.2020.129532
Xiaokang Miao 1 , Tianxiong Zhou 2 , Jingying Zhang 1 , Jingjie Xu 2 , Xiaomin Guo 2 , Hui Hu 2 , Xiaowei Zhang 1 , Mingning Hu 2 , Jingyi Li 1 , Wenle Yang 1 , Junqiu Xie 1 , Zhaoqing Xu 1 , Lingyun Mou 2
Affiliation  

BACKGROUND Hybridization is a useful strategy to bond the advantages of different peptides into novel constructions. We designed a series of AMPs based on the structures of a synthetic AMP KFA3 and a naturally-occurred host defense peptide substance P (SP) to obtain peptides retaining the high antibacterial activity of KFA3 and the immunomodulatory activity and low cytotoxicity of SP. METHODS Two repeats of KFA and different C terminal fragments of SP were hybridized, generating a series of novel AMPs (KFSP1-8). The antibacterial activities, host cell toxicity and immunomodulation were measured. The antibacterial mechanisms were investigated. RESULTS Hybrid peptides KFSP1-4 exerted substantial antibacterial activities against Gram-negative bacteria of standard strains and clinical drug-resistant isolates including E.coli, A.baumannii and P.aeruginosa, while showing little toxicity towards host cells. Compared with KFA3, moderate reduction in α-helix content and the interruption in α-helix continuality were indicated in CD spectra analysis and secondary-structure simulation in these peptides. Membrane permeabilization combined with time-kill studies and FITC-labeled imaging, indicated a selective membrane interaction of KFSP1 with bacteria cell membranes. By specially activating NK1 receptor, the hybrid peptides kept the ability of SP to induce intracellular calcium release and ERK1/2 phosphorylation, but unable to stimulate NF-κB phosphorylation. KFSP1 facilitated the survival of mouse macrophage RAW264.7, directly interacting with LPS and inhibiting the LPS-induced NF-κB phosphorylation and TNF-α expression. CONCLUSION Hybridization is a useful strategy to bond the advantages of different peptides. KFSP1 and its analogs are worth of advanced efforts to explore their potential applications as novel antimicrobial agents.

中文翻译:

具有潜在的抗菌活性和免疫调节作用的杂合肽的细胞选择性增强。

背景技术杂交是将不同肽的优点结合成新结构的有用策略。我们基于合成的AMP KFA3和天然存在的宿主防御肽物质P(SP)的结构设计了一系列AMP,以获得保留KFA3的高抗菌活性以及SP的免疫调节活性和低细胞毒性的肽。方法将KFA的两个重复序列和SP的不同C末端片段杂交,生成一系列新型AMP(KFSP1-8)。测量了抗菌活性,宿主细胞毒性和免疫调节。研究了抗菌机理。结果杂合肽KFSP1-4对标准菌株和临床耐药菌株包括大肠杆菌,鲍曼不动杆菌和P.的革兰氏阴性菌具有显着的抗菌活性。铜绿假单胞菌,对宿主细胞几乎没有毒性。与KFA3相比,这些肽的CD光谱分析和二级结构模拟显示α-螺旋含量适度降低和α-螺旋连续性中断。膜通透性与时间杀灭研究和FITC标记的成像相结合,表明KFSP1与细菌细胞膜的选择性膜相互作用。通过专门激活NK1受体,杂合肽保持SP诱导细胞内钙释放和ERK1 / 2磷酸化的能力,但不能刺激NF-κB磷酸化。KFSP1促进了小鼠巨噬细胞RAW264.7的存活,它直接与LPS相互作用并抑制LPS诱导的NF-κB磷酸化和TNF-α表达。结论杂交是结合不同肽的优点的有用策略。KFSP1及其类似物值得我们为探索其作为新型抗菌剂的潜在应用而付出的高级努力。
更新日期:2020-01-15
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