Engineered killer mimotopes: New synthetic peptides for antimicrobial therapy

W. Magliani, S. Conti, A. Salati, S. Arseni, L. Ravanetti, R. Frazzi, L. Polonelli

Research output: Contribution to journalArticle

Abstract

This review deals with a novel approach to produce synthetic antibiotic peptides (killer mimotopes), similar to those described for the conversion of epitopes into peptide mimotopes, allowing their use as surrogate vaccines. Synthetic peptides pertaining to the complementary determining regions (CDRs) of a recombinant antiidiotypic antibody (PaKTscFv), which mimic the wide spectrum of microbicidal activity of a killer toxin produced by the yeast Pichia anomala (PaKT), have proven to act as structural or functional mimotopes of PaKT. This activity appeared to be mediated by interaction with specific cell wall killer toxin receptors (KTRs), mainly constituted by β glucans. Killer mimotopes have shown in vitro an impressive microbicidal activity against Candida albicans. They were adopted as a model of PaKT- and PaKTscFv-susceptible microorganisms. Optimization through alanine scanning led to the generation of an engineered decapeptide (KP) of a CDR-L1 pertaining antibody fragment with an enhanced in vitro microbicidal activity. It had a potent therapeutic effect against experimental vaginal and systemic candidiasis in normal and immunodeficient mice caused by flucanozole susceptible and resistant yeast isolates. KP exerted a microbicidal activity in vitro against multidrug-resistant eukaryotic and prokaryotic pathogenic microorganisms, which was neutralized by interaction with laminarin (β 1,3-glucan). To our knowledge, KP represents the prototype of an engineered peptide fragment derived from a microbicidal recombinant antiidiotypic antibody. It is capable of exerting antimicrobial activity in vitro and a therapeutic effect in vivo presumably acting through interaction with the β glucan KTR component in the cell walls of pathogenic microorganisms.

Original languageEnglish
Pages (from-to)1793-1800
Number of pages8
JournalCurrent Medicinal Chemistry
Volume11
Issue number13
Publication statusPublished - Jul 2004

Keywords

  • Antiidiotypic antibiotics
  • Antiidiotypic therapy
  • Antimicrobial therapy
  • Killer mimotopes
  • Synthetic peptides
  • Yeast killer toxin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Organic Chemistry
  • Pharmacology

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