Enhanced cell selectivity of hybrid peptides with potential antimicrobial activity and immunomodulatory effect
Enhanced cell selectivity of hybrid peptides with potential antimicrobial activity and immunomodulatory effect
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具有潜在抗菌活性和免疫调节作用的杂合肽增强细胞选择性。
DOI：
10.1016/j.bbagen.2020.129532
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发表时间：
2020-04-01
影响因子：
3
通讯作者：
Mou, Lingyun
中科院分区：
文献类型：
--
作者：
Miao, Xiaokang;Zhou, Tianxiong;Mou, Lingyun
背景：杂交是将不同肽的优点结合到新结构中的有用策略。我们设计了一系列基于合成AMP KFA 3和天然存在的宿主防御肽P物质（SP）的结构的AMP，以获得保留KFA 3的高抗菌活性和SP的免疫调节活性和低细胞毒性的肽。方法：将两个重复的KFA与SP的不同C末端片段杂交，产生一系列新的AMP（KFSP 1 -8）。测定其抗菌活性、宿主细胞毒性和免疫调节作用。结果：杂合肽KFSP 1 -4对大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌等革兰阴性菌标准株和临床耐药株均有较强的抗菌活性，对宿主细胞毒性较小。与KFA 3相比，CD谱分析和二级结构模拟表明，α-螺旋含量适度降低，α-螺旋连续性中断。结合时间杀死研究和FITC标记的成像的膜透化，表明KFSP 1与细菌细胞膜的选择性膜相互作用。通过特异性激活NK 1受体，杂合肽保留了SP诱导细胞内钙释放和ERK 1/2磷酸化的能力，但不能刺激NF-κ B B磷酸化。结论：KFSP 1能促进小鼠巨噬细胞RAW 264. 7的存活，并能直接与LPS相互作用，抑制LPS诱导的NF-κ B磷酸化和TNF-α表达。KFSP 1及其类似物作为新型抗菌剂的潜在应用值得进一步研究。
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 alpha-helix content and the interruption in a-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-kappa B phosphorylation. KFSP1 facilitated the survival of mouse macrophage RAW264.7, directly interacting with LPS and inhibiting the LPS-induced NF-kappa B phosphorylation and TNF-alpha 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.