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 journalArticlepeer-review

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 2008

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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