A multivalent peptide library approach identifies a novel Shiga toxin inhibitor that induces aberrant cellular transport of the toxin
- 25 October 2006
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 20 (14), 2597-2599
- https://doi.org/10.1096/fj.06-6572fje
Abstract
Infection with Shiga toxin (Stx)-producing Escherichia coli O157:H7 causes bloody diarrhea and hemorrhagic colitis in humans, sometimes resulting in fatal systemic complications. Among the known Stx family members, Stx2 is responsible for the most severe forms of disease. Stx2 binds to target cells via multivalent interactions between its B-subunit pentamer and globotriaosyl ceramide. After binding, it is first retrogradely transported to the Golgi and then to the endoplasmic reticulum (ER). Using a multivalent peptide library approach, we identified a tetravalent peptide that exhibits a high affinity for the Stx2 B-subunit pentamer (KD=0.13 μM) and markedly inhibits Stx2 cytotoxicity. The tetravalent peptide exerted its inhibitory effects by inducing aberrant cellular transport of Stx2. Although the tetravalent peptide/Stx2 complex was incorporated into cells and translocated to the Golgi, this process was followed by the effective degradation of Stx2 in an acidic compartment rather than by its transfer to the ER. This peptide thoroughly protected mice from a fatal dose of E. coli O157:H7 even when administered after an established infection. Thus, the multivalent peptide library approach enabled the identification of a peptide-based Stx2 inhibitor that has remarkable therapeutic potency and appears to function by inducing aberrant cellular transport and degradation of Stx2.—Nishikawa, K., Watanabe, M., Kita, E., Igai, K., Omata, K., Yaffe, M. B., Natori, Y. A multivalent peptide library approach identifies a novel Shiga toxin inhibitor that induces aberrant cellular transport of the toxin.Keywords
Funding Information
- Precursory Research for Embryonic Science and Technology
This publication has 27 references indexed in Scilit:
- Structure of Shiga Toxin Type 2 (Stx2) from Escherichia coli O157:H7Journal of Biological Chemistry, 2004
- A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7Proceedings of the National Academy of Sciences, 2002
- A new biological agent for treatment of Shiga toxigenic Escherichia coli infections and dysentery in humansNature Medicine, 2000
- Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligandsNature, 2000
- Pathogenesis and Diagnosis of Shiga Toxin-Producing Escherichia coli InfectionsClinical Microbiology Reviews, 1998
- STRUCTURAL BASIS OF LECTIN-CARBOHYDRATE RECOGNITIONAnnual Review of Biochemistry, 1996
- Shiga and Shiga-like toxins.Microbiological Reviews, 1987
- The Association Between Idiopathic Hemolytic Uremic Syndrome and Infection by Verotoxin-Producing Escherichia coliThe Journal of Infectious Diseases, 1985
- Hemorrhagic Colitis Associated with a RareEscherichia coliSerotypeNew England Journal of Medicine, 1983
- SPORADIC CASES OF HAEMOLYTIC-URAEMIC SYNDROME ASSOCIATED WITH FAECAL CYTOTOXIN AND CYTOTOXIN-PRODUCING ESCHERICHIA COLI IN STOOLSThe Lancet, 1983