Multi-beta-S- and beta-N-galacto- and lactosides as substrates and inhibitors of T. cruzi trans-sialidase

ROSALIA AGUSTI; MARÍA EMILIA CANO; ALEJANDRO CAGNONI; MARIA FLORENCIA TESORIERO; MARÍA LAURA UHRIG; ROSA M. DE LEDERKREMER

Capital Federal

Simposio; 1er Simposio Argentino de Glicobiología (GlycoAr 2014); 2014

Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), el Instituto de Biología y Medicina Experimental (IBYME) y por la Fundación Instituto Leloir (FIL)

Trypanosoma cruzi, the agent of Chagas disease, does not synthesize sialic acid de novo. A parasite trans-sialidase (TcTS) activity transfers sialic acid from host glycoconjugates to terminal -galactopyranosyl groups in acceptor parasite substrates. TcTS probed to be essential for the parasite survival. We have previously determined that lactose analogs are inhibitors of this enzyme and that conjugation with multiarm polyethyleneglycol enhances their bioavailability in vivo. We hereby present the acceptor properties of a family of multivalent compounds bearing -S- or -N-galactose and lactose residues linked to sugar scaffolds. Most of them present a triazole ring and variable oligoethyleneglycol chains as biocompatible linkers. Tioglycosides, as well as N-glycosides, have the advantage of being highly resistant to enzymatic hydrolysis. Transfer reactions of sialic acid were performed using 3?-sialyllactose as sialic acid donor and recombinant TcTS, kindly given by researchers from IIB-UNSAM. The products were analyzed by high performance anion exchange chromatography with pulse amperometric detection (HPAEC-PAD). The ability of the different S-linked and N-linked glycosides as inhibitors of the TcTS was studied and compared. Most of the substrates were very good acceptors and inhibitors of the enzyme and the presence of polysialylated structures with up to 7 sialic acid residues was observed.