title: Glycan encapsulated gold nanoparticles selectively inhibit shiga toxins 1 and 2.
abstract: Shiga toxins (Stx) released by Escherichia coli O157:H7 and Shigella dysentriae cause life-threatening conditions that include hemolytic uremic syndrome (HUS), kidney failure, and neurological complications. Cellular entry is mediated by the B-subunit of the AB(5) toxin, which recognizes cell surface glycolipids present in lipid raft-like structures. We developed gold glyconanoparticles that present a multivalent display similar to the cell surface glycolipids to compete for these toxins. These highly soluble glyconanoparticles were nontoxic to the Vero monkey kidney cell line and protected Vero cells from Stx-mediated toxicity in a dose-dependent manner. The inhibition is highly dependent on the structure and density of the glycans; selective inhibition of Stx1 and the more clinically relevant Stx2 was achieved. Interestingly, natural variants of Stx2, Stx2c, and Stx2d possessing minimal amino acid variation in the receptor binding site of the B-subunit or changes in the A-subunit were not neutralized by either the Stx1- or Stx2-specific gold glyconanoparticles. Our results suggest that tailored glyconanoparticles that mimic the natural display of glycans in lipid rafts could serve as potential therapeutics for Stx1 and Stx2. However, a few amino acid changes in emerging Stx2 variants can change receptor specificity, and further research is needed to develop receptor mimics for the emerging variants of Stx2.
authors.affiliation: UC Chemical and Biosensors group, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA.
authors.forename: Ashish A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Cynthia
authors.initials: C
authors.lastname: Fuller
authors.forename: Henry
authors.initials: H
authors.lastname: Korman
authors.forename: Alison A
authors.initials: AA
authors.lastname: Weiss
authors.forename: Suri S
authors.initials: SS
authors.lastname: Iyer
mesh_terms: D000818:Animals; D001665:Binding Sites; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D019453:Escherichia coli O157 / Q000737:chemistry; D006046:Gold / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D053768:Metal Nanoparticles / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011134:Polysaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D022622:Shiga Toxin 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D012762:Shigella dysenteriae / Q000737:chemistry; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014709:Vero Cells
chemical_list: D008024:Ligands; D011134:Polysaccharides; D022622:Shiga Toxin 1; D022641:Shiga Toxin 2; D006046:Gold