Inhibition of the adherence of cholera toxin and the heat-labile enterotoxin of Escherichia coli to cell-surface GM1 by oligosaccharide-derivatized dendrimers

Jeffrey P. Thompson, Cara Lynne Schengrund

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42 Scopus citations

Abstract

The adherence of either cholera toxin or the heat-labile enterotoxin of Escherichia coli to monosialoganglioside gal(β1-3)galNAc(β1-4)[sialic acid (α2-3)]gal(β1-4)glcβ1-ceramide (GM1) present on the surface of epithelial cells lining the intestine is the first step of a series that results in the induction of a watery diarrhea. While cholera is more severe, both can lead to death as a result of dehydration. To determine the potential of defined multivalent oligosaccharides, synthesized by the covalent attachment of multiple phenylisothiocyanate (PITC) derivatives of gal(β1-3)galNAc(β1-4)[sialic acid(α2-3)]gal(β1-4)glc (oligo-GM1) to the arms of a poly(propylene imine) dendrimer, as therapeutic agents for these diseases, their ability to inhibit adherence of the toxins to cell surface-associated GM1 was determined. They not only inhibited choleragenoid (binding subunit of cholera toxin) binding to GM1-treated NCTC-2071 cells (chemically transformed murine fibroblasts) at 5°, but also inhibited adherence of the choleragenoid, cholera toxin, and heat-labile enterotoxin of E. coli to GM1-treated NCTC-2071 cells at 37°. Inhibition was observed whether the toxin was preincubated with the oligo-GM1-PITC-derivatized dendrimer prior to addition to cells or given just after the addition of the derivatized dendrimer to cells. The derivatized dendrimer had no effect on cell viability, as monitored by trypan blue exclusion. Blue-shifts in tryptophan fluorescence emission spectra maxima induced by adherence of either choleragenoid, cholera holotoxin, or the heat-labile enterotoxin of E. coli to oligo-GM1-PITC-derivatized dendrimers were similar to those induced by adherence to GM1 or oligo-GM1. Comparable shifts were not observed when the toxins were incubated with gangliosides that fail to function as receptors. Copyright (C) 1998 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)591-597
Number of pages7
JournalBiochemical Pharmacology
Volume56
Issue number5
DOIs
StatePublished - Sep 1 1998

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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