期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 17, 页码 7991-8000出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01079
关键词
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资金
- National Natural Science Foundation of China [31672456, 31572444, 31572445, 31372346]
- Project of the National Support Program for Science and Technology in China [2013BAD10B02]
- AMP Direction of the National Innovation Program of Agricultural Science and Technology in CAAS [CAAS-ASTIP-2013-FRI-02]
- Key Project of Alternatives to Antibiotics for Feed Usages [CAAS-ZDXT2018008]
The poor penetration ability of antimicrobial agents limits their use in the treatment of intracellular bacteria. In this study, the conjugate CNC (6) was generated by connecting the cell-penetrating peptide Tat(11) (1) and marine peptide N6 (2) via a cathepsin-cleavable linker, and the C-terminal aminated N6 (7) and CNC (8) were first designed and synthesized to eliminate intracellular Salmonellae Typhimurium. The cellular uptake of 6 and stability of 7 were higher than those of 2, and conjugates 6, 8, and 7 had almost no hemolysis and cytotoxicity. The antibacterial activities of 6, 8, and 7 against S. Typhimurium in RAW264.7 cells were increased by 67.2-76.2%, 98.6-98.9%, and 96.3-97.6%, respectively. After treatment with 1-2 mu mol/kg of 6, 8, or 7, the survival of the S. Typhimurium-infected mice was 66.7-100%, higher than that of 2 (33.4-66.7%). This result suggested that 6, 8, and 7 may be excellent candidates for novel antimicrobial agents to treat intracellular pathogens.
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