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Insect peptides with improved protease‐resistance protect mice against bacterial infection
Author(s) -
Otvos Laszlo,
Bokonyi Krisztina,
Varga Istvan,
Ertl Hildegund C. J.,
Hoffmann Ralf,
Bulet Philippe,
Otvos Balint I.,
Wade John D.,
Mcmanus Ailsa M.,
Craik David J.
Publication year - 2000
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.9.4.742
Subject(s) - in vivo , in vitro , peptide , protease , escherichia coli , antimicrobial peptides , antimicrobial , toxicity , biochemistry , biology , antibacterial activity , cyclic peptide , microbiology and biotechnology , chemistry , bacteria , enzyme , genetics , organic chemistry , gene
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.