Identifying Efficient Clostridium difficile Toxin A Binders with a Multivalent Neo-Glycoprotein Glycan Library

0509779 - MBÚ 2020 RIV US eng J - Journal Article
Heine, V. - Boesveld, S. - Pelantová, Helena - Křen, Vladimír - Trautwein, Ch. - Strnad, P. - Elling, L.
Identifying Efficient Clostridium difficile Toxin A Binders with a Multivalent Neo-Glycoprotein Glycan Library.
Bioconjugate Chemistry. Roč. 30, č. 9 (2019), s. 2373-2383. ISSN 1043-1802. E-ISSN 1520-4812
R&D Projects: GA MŠMT(CZ) LTC18041
Institutional support: RVO:61388971
Keywords : helicobacter-pylori * lecitin * oligosaccharides
OECD category: Biochemistry and molecular biology
Impact factor: 4.031, year: 2019
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.bioconjchem.9b00486

Clostridium difficile infections cause gastrointestinal disorders and can lead to life-threatening conditions. The symptoms can vary from severe diarrhea to the formation of pseudomembranous colitis and therefore trigger a need for new therapies. The initial step of disease is the binding of the bacterial enterotoxins toxin A and B to the cell surface of epithelial intestinal cells. Scavenging of the toxins is crucial to inhibit their fatal effect in the human body and circumvent the administration of antibiotics. Cell surface glycans are common as ligands for TcdA. Although crucial for carbohydrate-protein interactions, a multivalent presentation of glycans for binding has been hardly considered. Here, we establish a neoglycoprotein-based glycan library to identify an effective multivalent glycan ligand for TcdA. It comprises 40 different glycan epitopes based on N-acetyllactosamine precursors. Nine structures exhibit strong binding of the receptor domain. Among them, the Lewis(y)-Lewis(x)-epitope shows the best performance for binding both the receptor domain and the holotoxin. Therefore, the glycan was synthesized de novo and coupled to BSA as a scaffold for multivalent presentation. The corresponding neo-glycoprotein facilitates the proper scavenging of TcdA in vitro and effectively protects HT29 cells from TcdA-induced cell damage.
Permanent Link: http://hdl.handle.net/11104/0300413