title: Identification of a peptide-based neutralizer that potently inhibits both Shiga toxins 1 and 2 by targeting specific receptor-binding regions.
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.
authors.affiliation: Doshisha University, Kyoto, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Tsutsuki
authors.forename: Miho
authors.initials: M
authors.lastname: Watanabe-Takahashi
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Takenaka
authors.forename: Eiji
authors.initials: E
authors.lastname: Kita
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nishikawa
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002470:Cell Survival; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004927:Escherichia coli Infections / Q000188:drug therapy; D019453:Escherichia coli O157 / Q000472:pathogenicity; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D021122:Protein Subunits; D022622:Shiga Toxin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D013047:Specific Pathogen-Free Organisms; D014709:Vero Cells
chemical_list: D019151:Peptide Library; D010455:Peptides; D021122:Protein Subunits; D022622:Shiga Toxin 1; D022641:Shiga Toxin 2
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