Abstract |
The host-defense peptide, esculentin-2CHa ( GFSSIFRGVA(10)KFASKGLGK D(20)LAKLGVDLVA(30) CKISKQC) shows potent (MIC≤6 μM) growth inhibitory activity against clinical isolates of multidrug-resistant strains of Staphylococcus aureus, Acinetobacter baumannii, and Stenotrophomonas maltophilia and differential cytotoxic activity against human erythrocytes (LC(50)=150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC(50)=10 μM). Esculentin-2CHa significantly (P<0.01) stimulates the release of the anti-inflammatory cytokine IL-10 by mouse lymphoid cells and elevates its production after stimulation with concanavalin A and significantly (P<0.05) stimulates TNF-α production by peritoneal macrophages. Effects on IL-6 and IL-1β production were not significant. Removal of the hydrophobic N-terminal hexapeptide (GFSSIF) from esculentin-2CHa results in abolition of growth inhibitory activity against S. aureus and cytotoxic activity against erythrocytes and A549 cells as well as a marked (≥16-fold) reduction in potency against A. baumannii and S. maltophilia. The primary structure of esculentin-2 has been poorly conserved between frog species but evolutionary pressure has acted to maintain the hydrophobic character of this N-terminal hexapeptide sequence. Removal of the cyclic C-terminal domain (CKISKQC) and replacement of the Cys(31) and Cys(37) residues by serine resulted in appreciable decreases in cytotoxicity against all microorganisms and against mammalian cells. The more cationic [D20K, D27K] analog showed a modest increase in potency against all microorganisms (up to 4-fold) but a marked increase in cytotoxicity against erythrocytes (LC(50)=11 μM) and A549 cells (LC(50)=3 μM).
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Authors | Samir Attoub, Milena Mechkarska, Agnes Sonnevend, Gordana Radosavljevic, Ivan Jovanovic, Miodrag L Lukic, J Michael Conlon |
Journal | Peptides
(Peptides)
Vol. 39
Pg. 95-102
(Jan 2013)
ISSN: 1873-5169 [Electronic] United States |
PMID | 23159562
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
Chemical References |
- Anti-Bacterial Agents
- Antimicrobial Cationic Peptides
- Antineoplastic Agents
- Cytokines
- Lipopolysaccharides
- esculentin-2CHa, Lithobates chiricahuensis
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Topics |
- Amino Acid Sequence
- Animals
- Anti-Bacterial Agents
(pharmacology)
- Antimicrobial Cationic Peptides
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Cytokines
(metabolism)
- Erythrocytes
(drug effects)
- Escherichia coli
(drug effects)
- Humans
- Hydrophobic and Hydrophilic Interactions
- Inhibitory Concentration 50
- Lipopolysaccharides
(pharmacology)
- Macrophages, Peritoneal
(drug effects, immunology, metabolism)
- Mice
- Microbial Sensitivity Tests
- Molecular Sequence Data
- Protein Structure, Secondary
- Ranidae
- Staphylococcus aureus
(drug effects)
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