Esculentin-2CHa: A host-defense peptide with differential cytotoxicity against bacteria, erythrocytes and tumor cells

Samir Attoub; Milena Mechkarska; Agnes Sonnevend; Gordana Radosavljevic; Ivan Jovanovic; Miodrag L. Lukic; J. Michael Conlon

doi:10.1016/j.peptides.2012.11.004

Esculentin-2CHa: A host-defense peptide with differential cytotoxicity against bacteria, erythrocytes and tumor cells

Samir Attoub, Milena Mechkarska, Agnes Sonnevend, Gordana Radosavljevic, Ivan Jovanovic, Miodrag L. Lukic, J. Michael Conlon

School of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

The host-defense peptide, esculentin-2CHa (GFSSIFRGVA¹⁰KFASKGLGK D²⁰LAKLGVDLVA³⁰ 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 (LC₅₀ = 150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC₅₀ = 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 Cys³¹ and Cys³⁷ 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 (LC₅₀ = 3 μM).

Original language	English
Pages (from-to)	95-102
Number of pages	8
Journal	Peptides
Volume	39
Issue number	1
DOIs	https://doi.org/10.1016/j.peptides.2012.11.004
Publication status	Published (in print/issue) - Jan 2013

Bibliographical note

Funding Information:
This work was supported by a Faculty Support Grant and a University Research Grant ( G00000900 ) from U.A.E. University and by a grant from the Terry Fox Fund for Cancer Research . The authors thank Manju Prajeep, Kholoud Arafat, and Hama Arafat for technical assistance. The authors thank Prof. P.R. Flatt, University of Ulster, U.K. for a gift of peptides.

Keywords

Anticancer
Antimicrobial
Esculentin-2
Frog skin peptide
Hemolytic
Immunomodulatory

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10.1016/j.peptides.2012.11.004

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title = "Esculentin-2CHa: A host-defense peptide with differential cytotoxicity against bacteria, erythrocytes and tumor cells",

abstract = "The host-defense peptide, esculentin-2CHa (GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30 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 (LC50 = 150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC50 = 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 Cys31 and Cys37 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 (LC50 = 3 μM).",

keywords = "Anticancer, Antimicrobial, Esculentin-2, Frog skin peptide, Hemolytic, Immunomodulatory",

author = "Samir Attoub and Milena Mechkarska and Agnes Sonnevend and Gordana Radosavljevic and Ivan Jovanovic and Lukic, {Miodrag L.} and Conlon, {J. Michael}",

note = "Funding Information: This work was supported by a Faculty Support Grant and a University Research Grant ( G00000900 ) from U.A.E. University and by a grant from the Terry Fox Fund for Cancer Research . The authors thank Manju Prajeep, Kholoud Arafat, and Hama Arafat for technical assistance. The authors thank Prof. P.R. Flatt, University of Ulster, U.K. for a gift of peptides.",

year = "2013",

month = jan,

doi = "10.1016/j.peptides.2012.11.004",

language = "English",

volume = "39",

pages = "95--102",

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T2 - A host-defense peptide with differential cytotoxicity against bacteria, erythrocytes and tumor cells

AU - Attoub, Samir

AU - Mechkarska, Milena

AU - Sonnevend, Agnes

AU - Radosavljevic, Gordana

AU - Jovanovic, Ivan

AU - Lukic, Miodrag L.

AU - Conlon, J. Michael

N1 - Funding Information: This work was supported by a Faculty Support Grant and a University Research Grant ( G00000900 ) from U.A.E. University and by a grant from the Terry Fox Fund for Cancer Research . The authors thank Manju Prajeep, Kholoud Arafat, and Hama Arafat for technical assistance. The authors thank Prof. P.R. Flatt, University of Ulster, U.K. for a gift of peptides.

PY - 2013/1

Y1 - 2013/1

N2 - The host-defense peptide, esculentin-2CHa (GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30 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 (LC50 = 150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC50 = 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 Cys31 and Cys37 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 (LC50 = 3 μM).

AB - The host-defense peptide, esculentin-2CHa (GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30 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 (LC50 = 150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC50 = 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 Cys31 and Cys37 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 (LC50 = 3 μM).

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KW - Antimicrobial

KW - Esculentin-2

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KW - Hemolytic

KW - Immunomodulatory

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Esculentin-2CHa: A host-defense peptide with differential cytotoxicity against bacteria, erythrocytes and tumor cells

Abstract

Bibliographical note

Keywords

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