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Insect peptides with improved protease-resistance protect mice against bacterial infection

Published online by Cambridge University Press:  01 April 2000

LASZLO OTVOS
Affiliation:
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104
KRISZTINA BOKONYI
Affiliation:
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104
ISTVAN VARGA
Affiliation:
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104
BALINT I. OTVOS
Affiliation:
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104 Unité Propre du CNRS No. 9022, “Réponse Immunitaire et Développement chez les Insectes,” Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg Cedex, France
RALF HOFFMANN
Affiliation:
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104 Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Düsseldorf, Germany
HILDEGUND C.J. ERTL
Affiliation:
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104
JOHN D. WADE
Affiliation:
Howard Florey Institute, Parkville 3052, Victoria, Australia
AILSA M. McMANUS
Affiliation:
Centre for Drug Design and Development, University of Queensland, Brisbane 4072, Queensland, Australia
DAVID J. CRAIK
Affiliation:
Centre for Drug Design and Development, University of Queensland, Brisbane 4072, Queensland, Australia
PHILIPPE BULET
Affiliation:
Unité Propre du CNRS No. 9022, “Réponse Immunitaire et Développement chez les Insectes,” Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg Cedex, France
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Abstract

At a time of the emergence of drug-resistant bacterial strains, the development of antimicrobial compounds with novel mechanisms of action is of considerable interest. Perhaps the most promising among these is a family of antibacterial peptides originally isolated from insects. These were shown to act in a stereospecific manner on an as-yet unidentified target bacterial protein. One of these peptides, drosocin, is inactive in vivo due to the rapid decomposition in mammalian sera. However, another family member, pyrrhocoricin, is significantly more stable, has increased in vitro efficacy against Gram-negative bacterial strains, and if administered alone, as we show here, is devoid of in vitro or in vivo toxicity. At low doses, pyrrhocoricin protected mice against Escherichia coli infection, but at a higher dose augmented the infection of compromised animals. Analogs of pyrrhocoricin were, therefore, synthesized to further improve protease resistance and reduce toxicity. A linear derivative containing unnatural amino acids at both termini showed high potency and lack of toxicity in vivo and an expanded cyclic analog displayed broad activity spectrum in vitro. The bioactive conformation of native pyrrhocoricin was determined by nuclear magnetic resonance spectroscopy, and similar to drosocin, reverse turns were identified as pharmacologically important elements at the termini, bridged by an extended peptide domain. Knowledge of the primary and secondary structural requirements for in vivo activity of these peptides allows the design of novel antibacterial drug leads.

Type
Research Article
Copyright
© 2000 The Protein Society

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