Effect of aminoisobutyric acid (Aib) substitutions on the antimicrobial and cytolytic activities of the frog skin peptide, temporin-1DRa

J. Michael Conlon, Rokaya Al-Kharrge, Eman Ahmed, Haider Raza, Sehamuddin Galadari, Eric Condamine

    Research output: Contribution to journalArticle

    Abstract

    Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged frog Rana draytonii, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by its toxicity against mammalian cells. The cytolytic properties of cationic α-helical peptides are determined by a complex interaction between cationicity, hydrophobicity, conformation, and amphipathicity. This study has investigated the cytolytic properties of conformationally constrained analogs of temporin-1DRa containing α-aminoisobutyric acid (Aib) substitutions. Cytolytic activity was determined against the bacteria Escherichia coli and Staphylococcus aureus, the opportunistic yeast pathogen, Candida albicans, human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. Aib substitutions at Gly4, Asn8, and Ala10 increased both % helicity, determined in methanol solution, and hydrophobicity resulting in increases in both antimicrobial potencies and toxicities against the mammalian cells. Substitution at Leu6 resulted in an appreciable decrease in cytolytic activity against all cells whereas the substitutions at His1, Phe2, Leu3, Thr5, and Val7 had only minor effects on activity. Substitutions at Leu9, Ile13, Leu14 produced analogs with decreased helicity and hydrophobicity that retained activity against microorganisms but showed appreciably lower cytolytic activities against mammalian cells. In particular, the fourfold increase in therapeutic index [ratio of LC50 against erythrocytes to minimum inhibitory concentration (MIC) against microorganisms] of [Aib13]temporin-1DRa identifies it as a compound with potential for development as a therapeutically valuable anti-infective agent.

    Original languageEnglish (US)
    Pages (from-to)2075-2080
    Number of pages6
    JournalPeptides
    Volume28
    Issue number10
    DOIs
    StatePublished - Oct 1 2007

    Fingerprint

    Aminoisobutyric Acids
    Anura
    Skin
    Substitution reactions
    Hydrophobicity
    Peptides
    Hydrophobic and Hydrophilic Interactions
    Cells
    Microorganisms
    Toxicity
    Erythrocytes
    Ranidae
    Candida
    Microbial Sensitivity Tests
    Pathogens
    Fibroblasts
    Anti-Infective Agents
    Candida albicans
    Yeast
    Escherichia coli

    Keywords

    • α-Aminoisobutyric acid
    • Amphipathic α-helix
    • Antimicrobial
    • Cytolysis
    • Frog skin
    • Temporin

    ASJC Scopus subject areas

    • Biochemistry
    • Physiology
    • Endocrinology
    • Cellular and Molecular Neuroscience

    Cite this

    Effect of aminoisobutyric acid (Aib) substitutions on the antimicrobial and cytolytic activities of the frog skin peptide, temporin-1DRa. / Michael Conlon, J.; Al-Kharrge, Rokaya; Ahmed, Eman; Raza, Haider; Galadari, Sehamuddin; Condamine, Eric.

    In: Peptides, Vol. 28, No. 10, 01.10.2007, p. 2075-2080.

    Research output: Contribution to journalArticle

    Michael Conlon, J. ; Al-Kharrge, Rokaya ; Ahmed, Eman ; Raza, Haider ; Galadari, Sehamuddin ; Condamine, Eric. / Effect of aminoisobutyric acid (Aib) substitutions on the antimicrobial and cytolytic activities of the frog skin peptide, temporin-1DRa. In: Peptides. 2007 ; Vol. 28, No. 10. pp. 2075-2080.
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    abstract = "Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged frog Rana draytonii, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by its toxicity against mammalian cells. The cytolytic properties of cationic α-helical peptides are determined by a complex interaction between cationicity, hydrophobicity, conformation, and amphipathicity. This study has investigated the cytolytic properties of conformationally constrained analogs of temporin-1DRa containing α-aminoisobutyric acid (Aib) substitutions. Cytolytic activity was determined against the bacteria Escherichia coli and Staphylococcus aureus, the opportunistic yeast pathogen, Candida albicans, human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. Aib substitutions at Gly4, Asn8, and Ala10 increased both {\%} helicity, determined in methanol solution, and hydrophobicity resulting in increases in both antimicrobial potencies and toxicities against the mammalian cells. Substitution at Leu6 resulted in an appreciable decrease in cytolytic activity against all cells whereas the substitutions at His1, Phe2, Leu3, Thr5, and Val7 had only minor effects on activity. Substitutions at Leu9, Ile13, Leu14 produced analogs with decreased helicity and hydrophobicity that retained activity against microorganisms but showed appreciably lower cytolytic activities against mammalian cells. In particular, the fourfold increase in therapeutic index [ratio of LC50 against erythrocytes to minimum inhibitory concentration (MIC) against microorganisms] of [Aib13]temporin-1DRa identifies it as a compound with potential for development as a therapeutically valuable anti-infective agent.",
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    AU - Michael Conlon, J.

    AU - Al-Kharrge, Rokaya

    AU - Ahmed, Eman

    AU - Raza, Haider

    AU - Galadari, Sehamuddin

    AU - Condamine, Eric

    PY - 2007/10/1

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    N2 - Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged frog Rana draytonii, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by its toxicity against mammalian cells. The cytolytic properties of cationic α-helical peptides are determined by a complex interaction between cationicity, hydrophobicity, conformation, and amphipathicity. This study has investigated the cytolytic properties of conformationally constrained analogs of temporin-1DRa containing α-aminoisobutyric acid (Aib) substitutions. Cytolytic activity was determined against the bacteria Escherichia coli and Staphylococcus aureus, the opportunistic yeast pathogen, Candida albicans, human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. Aib substitutions at Gly4, Asn8, and Ala10 increased both % helicity, determined in methanol solution, and hydrophobicity resulting in increases in both antimicrobial potencies and toxicities against the mammalian cells. Substitution at Leu6 resulted in an appreciable decrease in cytolytic activity against all cells whereas the substitutions at His1, Phe2, Leu3, Thr5, and Val7 had only minor effects on activity. Substitutions at Leu9, Ile13, Leu14 produced analogs with decreased helicity and hydrophobicity that retained activity against microorganisms but showed appreciably lower cytolytic activities against mammalian cells. In particular, the fourfold increase in therapeutic index [ratio of LC50 against erythrocytes to minimum inhibitory concentration (MIC) against microorganisms] of [Aib13]temporin-1DRa identifies it as a compound with potential for development as a therapeutically valuable anti-infective agent.

    AB - Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged frog Rana draytonii, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by its toxicity against mammalian cells. The cytolytic properties of cationic α-helical peptides are determined by a complex interaction between cationicity, hydrophobicity, conformation, and amphipathicity. This study has investigated the cytolytic properties of conformationally constrained analogs of temporin-1DRa containing α-aminoisobutyric acid (Aib) substitutions. Cytolytic activity was determined against the bacteria Escherichia coli and Staphylococcus aureus, the opportunistic yeast pathogen, Candida albicans, human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. Aib substitutions at Gly4, Asn8, and Ala10 increased both % helicity, determined in methanol solution, and hydrophobicity resulting in increases in both antimicrobial potencies and toxicities against the mammalian cells. Substitution at Leu6 resulted in an appreciable decrease in cytolytic activity against all cells whereas the substitutions at His1, Phe2, Leu3, Thr5, and Val7 had only minor effects on activity. Substitutions at Leu9, Ile13, Leu14 produced analogs with decreased helicity and hydrophobicity that retained activity against microorganisms but showed appreciably lower cytolytic activities against mammalian cells. In particular, the fourfold increase in therapeutic index [ratio of LC50 against erythrocytes to minimum inhibitory concentration (MIC) against microorganisms] of [Aib13]temporin-1DRa identifies it as a compound with potential for development as a therapeutically valuable anti-infective agent.

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    KW - Amphipathic α-helix

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    KW - Cytolysis

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