Design of potent, non-toxic antimicrobial agents based upon the naturally occurring frog skin peptides, ascaphin-8 and peptide XT-7

J. Michael Conlon, Sehamuddin Galadari, Haider Raza, Eric Condamine

Research output: Contribution to journalArticle

Abstract

The frog skin peptides, ascaphin-8 (GFKDLLKGAAKALVKTVLF.NH2) and XT-7 (GLLGPLLKIAAKVGSNLL.NH2), show broad-spectrum antimicrobial activity but their therapeutic potential is limited by toxicity against mammalian cells. Circular dichroism spectra demonstrate that the peptides adopt an amphipathic α-helical conformation in a membrane-mimetic solvent. This study has investigated the cytolytic properties of analogs containing selected amino acid substitutions that increase cationicity while maintaining amphipathicity. Substitutions at Ala10, Val14, and Leu18 in ascaphin-8 by either l-Lys or d-Lys produced peptides that retained antimicrobial activity against the bacteria Escherichia coli and Staphylococcus aureus and the opportunistic yeast pathogen, Candida albicans but showed appreciably reduced toxicities (>10-fold) against human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. The improved therapeutic index of the l-Lys18 and d-Lys18 analogs correlated with a decrease in % helicity and in effective hydrophobicity. Substitution of Gly4 by l-Lys in XT-7 produced an analog with high potency against micro-organisms (MIC ≤ 25 mu;m) but low cytolytic activity against erythrocytes (LD50 > 500 mu;m) and this increase in therapeutic index also correlated with decreased helicity and hydrophobicity. Analogs of XT-7 with increased cationicity, containing multiple substitutions by l-Lys, not only displayed increased antimicrobial potencies, particularly against Candida albicans (MIC ≤ 6 mu;m), but also increased hemolytic activities.

Original languageEnglish (US)
Pages (from-to)58-64
Number of pages7
JournalChemical Biology and Drug Design
Volume72
Issue number1
DOIs
StatePublished - Jul 1 2008

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Anti-Infective Agents
Anura
Skin
Substitution reactions
Candida albicans
Hydrophobic and Hydrophilic Interactions
Peptides
Candida
Hydrophobicity
Erythrocytes
Toxicity
Lethal Dose 50
Amino Acid Substitution
Circular Dichroism
Staphylococcus aureus
Hepatocellular Carcinoma
Pathogens
Fibroblasts
Therapeutics
Yeasts

Keywords

  • Amphipathic α-helix
  • Antimicrobial
  • Ascaphin-8
  • Cytolysis
  • Peptide XT-7

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Design of potent, non-toxic antimicrobial agents based upon the naturally occurring frog skin peptides, ascaphin-8 and peptide XT-7. / Michael Conlon, J.; Galadari, Sehamuddin; Raza, Haider; Condamine, Eric.

In: Chemical Biology and Drug Design, Vol. 72, No. 1, 01.07.2008, p. 58-64.

Research output: Contribution to journalArticle

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