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Hydrophobic modification improves the delivery of cell-penetrating peptides to eliminate intracellular pathogens in animals

文献类型： 外文期刊

作者： Tang, Qi 1 ; Tan, Peng 1 ; Dai, Zhaolai 1 ; Wang, Tao 2 ; Xu, Shenrui 1 ; Ding, Yakun 3 ; Jin, Junqi 1 ; Zhang, Xin 1 ; Zhang, Yucheng 1 ; Zhou, Chenlong 1 ; Yue, Zitian 1 ; Fu, Huiyang 1 ; Yan, Junshu 4 ; Ma, Xi 1 ;

作者机构： 1.China Agr Univ, Coll Anim Sci & Technol, State Key Lab Anim Nutr, Beijing 100193, Peoples R China

2.Henan Univ Sci & Technol, Coll Anim Sci, Luoyang Key Lab Anim Genet & Breeding, Luoyang 471003, Peoples R China

3.Zhengzhou Univ, Sch Agr Sci, Henan Int Joint Lab Crop Gene Resource & Improveme, Zhengzhou 450001, Peoples R China

4.Jiangsu Acad Agr Sci, Inst Anim Sci, Nanjing, Peoples R China

关键词： Intracellular targeting; Cell penetrating peptide; Antimicrobial peptide; Intracellular pathogens; Action mechanism

期刊名称：ACTA BIOMATERIALIA （ 影响因子：9.7； 五年影响因子：9.9 ）

ISSN： 1742-7061

年卷期： 2023 年 157 卷

页码：

收录情况： SCI

摘要： Infections induced by intracellular pathogens are difficult to eradicate due to poor penetration of an-timicrobials into cell membranes. It is of great importance to develop a new generation of antibacterial agents with dual functions of efficient cell penetration and bacterial inhibition. In this study, the associ-ation between hydrophobicity and cell-penetrating peptide delivery efficiency was investigated by frag-ment interception and hydrophobicity modification of natural porcine antimicrobial peptide PR-39 and the combination of cationic cell-penetrating peptide (R6) with antimicrobial peptide fragments modified with hydrophobic residues. The chimeric peptides P3I7 and P3L7, obtained through biofunctional screen-ing, exhibited potent broad-spectrum antibacterial activity and low cytotoxicity. Moreover, P3I7 and P3L7 can effectively penetrate cells to eliminate intracellular pathogens mainly through endocytosis. The mem-brane destruction mechanism makes the peptides fast sterilizers and less prone to developing drug re-sistance. Finally, their good biocompatibility and antibacterial infection effects were verified in mice and piglets. To conclude, the chimeric peptides P3I7 and P3L7 show great potential as affordable and effec-tive antimicrobial agents and may serve as ideal candidates for the treatment of intracellular bacterial infections.Statement of significanceThe low permeability of antibacterial drugs makes infections induced by intracellular bacteria extremely difficult to treat. To address this issue, we designed chimeric peptides with dual cell-penetrating and antibacterial functions. The active peptides P3I7 and P3L7, acquired through functional screening have strong broad-spectrum antibacterial activity and powerful bactericidal effects against intracellular Staphy-lococcus aureus. The membrane permeation mechanism of P3I7 and P3L7 against bacteria endows fast bactericidal activity with low drug resistance. The biosafety and antibacterial activity of P3I7 and P3L7 were also validated by in vivo trials. This study provides an ideal drug candidate against intracellular bacterial infections.(c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

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