Elastase-Activated Antimicrobial Peptide for a Safer Pulmonary Treatment of Cystic Fibrosis Infections

被引:6
作者
Degasperi, Margherita [1 ,2 ]
Sgarra, Riccardo [1 ]
Mardirossian, Mario [1 ]
Pacor, Sabrina [1 ]
Maschio, Massimo [3 ]
Scocchi, Marco [1 ]
机构
[1] Univ Trieste, Dept Life Sci, I-34127 Trieste, Italy
[2] ARGO Open Lab Platform Genome Sequencing, AREA Sci Pk, I-34149 Trieste, Italy
[3] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, I-34134 Trieste, Italy
来源
ANTIBIOTICS-BASEL | 2022年 / 11卷 / 03期
关键词
antimicrobial peptide; cystic fibrosis; pro-drug; elastase; Pseudomonas aeruginosa; HOST-DEFENSE PEPTIDES; NEUTROPHIL ELASTASE; IN-VITRO; PRODRUGS; ANTIBACTERIAL;
D O I
10.3390/antibiotics11030319
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
As bioactive small proteins with antimicrobial and immunomodulatory activities that are naturally produced by all living organisms, antimicrobial peptides (AMPs) have a marked potential as next-generation antibiotics. However, their development as antibacterial agents is limited by low stability and cytotoxicity. D-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, has shown good antibacterial and anti-inflammatory activities but also a non-negligible cytotoxicity against eukaryotic cell lines. In this study, a prodrug has been developed that extends the peptide with a negatively charged, inactivating sequence containing the cleavage site for neutrophil elastase (NE). The ultimate goal was to allow the activation of D-BMAP18 by endogenous elastase only at the site of infection/inflammation, enabling a slow and targeted release of the pharmacologically active peptide. In vitro activation of Pro-D-BMAP18 was confirmed using purified NE. Its antimicrobial and cytotoxic activities were tested in the presence and absence of elastase and compared to those of the parental form. The prodrug had minimal activity in the absence of elastase, while its proteolysis product retained an appreciable antimicrobial activity but lower cytotoxicity. Moreover, Pro-D-BMAP18 was found to be correctly converted to D-BMAP18 in the presence of CF sputum as a model of the lung environment and showed good antimicrobial activity under these conditions.
引用
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页数:11
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