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Identifying efficient Clostridium difficile toxin A binders with a multivalent neo-glycoprotein glycan library.

V. Heine,Sarah Boesveld,H. Pelantová,V. Křen,C. Trautwein,P. Strnad,L. Elling

Published 2019 in Bioconjugate chemistry

ABSTRACT

Clostridium difficile infections cause gastrointestinal disorders and can lead to life-threatening conditions. The symp-toms 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 epithe-lial intestinal cells. Scavenging of the toxins is crucial to inhibit their fatal effect in the human body and circumvent ad-ministration of antibiotics. Cell surface glycans are common as ligands for TcdA. Although crucial for carbohydrate-protein interactions, multivalent presentation of glycans for binding has been hardly considered. Here, we establish a neo-glycoprotein-based glycan library to identify an effective multivalent glycan ligand for TcdA. It comprises 40 differ-ent glycan epitopes based on N-acetyllactosamine precursors. Nine structures exhibit strong binding of the receptor do-main. Among them, the Lewisy-Lewisx-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 proper scavenging of TcdA in vitro and effectively protects HT29 cells from TcdA-induced cell damage.

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