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Infect Immun ; 81(6): 2133-8, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23545297

ABSTRACT

Shiga toxin (Stx) is a major virulence factor of enterohemorrhagic Escherichia coli that occasionally causes fatal systemic complications. We recently developed a tetravalent peptide (PPP-tet) that neutralizes the cytotoxicity of Stx2 using a multivalent peptide library approach. In this study, we used this technique to identify a series of tetravalent peptides that bound to Stx1, another major Stx family member, with high affinity by targeting one receptor-binding site of the B subunit. One peptide, MMA-tet, markedly inhibited Stx1 and Stx2 cytotoxicity with greater potency than PPP-tet. After forming a complex with Stx1 through its specific receptor-binding region, MMA-tet did not affect vesicular transport of the toxin to the endoplasmic reticulum but substantially rescued inhibition of the protein synthesis induced by Stx1. Oral application of MMA-tet protected mice from a fatal dose of an E. coli O157:H7 strain producing both toxins. MMA-tet may be a promising therapeutic agent against the infection.


Subject(s)
Peptides/pharmacology , Shiga Toxin 1/antagonists & inhibitors , Shiga Toxin 2/antagonists & inhibitors , Amino Acid Substitution , Animals , Cell Survival , Chlorocebus aethiops , Endoplasmic Reticulum/metabolism , Enzyme-Linked Immunosorbent Assay , Escherichia coli Infections/drug therapy , Escherichia coli O157/pathogenicity , Female , Mice , Mice, Inbred C57BL , Peptide Library , Peptides/chemistry , Peptides/therapeutic use , Protein Subunits , Shiga Toxin 1/metabolism , Shiga Toxin 1/toxicity , Shiga Toxin 2/metabolism , Shiga Toxin 2/toxicity , Specific Pathogen-Free Organisms , Vero Cells
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