Chagas disease (CD) is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. It affects 6-7 millions of people worldwide, predominantly in Latin America, where the parasite is endemic. The disease is also becoming an increasing public health threat to the U.S., where it is estimated that about 300,000 people are chronically infected. The complex cell surface of the parasite’s infective trypomastigote stage is densely coated with glycosylphosphatidylinositol (GPI)-anchored mucin-like glycoproteins (tGPI-mucins); specifically rich in α-galactopyranosyl (α-Gal) O-linked glycans, which are highly immunogenic to humans and Old-World nonhuman primates. The linear trisaccharide Galα1-3Galβ1-4GlcNAcα, is the only O-linked glycan fully elucidated to date, which represents approximately 10% of all tGPI-mucin glycans. The structures of the remaining 90% O-glycans are still elusive, but it is known that branched glycans with terminal, nonreducing α-Gal moieties are predominant. It is also known that protective T. cruzi-specific anti-α-Gal antibodies, present in the sera of both acute and chronic CD patients (CD anti-α-Gal Abs), strongly recognize tGPI-mucin O-glycans with terminal nonreducing α-Gal moieties. MS/MS fragmentation analysis of O-glycans derived from T. cruzi GPI-mucins has suggested novel partial structures of prevalent branched O-linked glycans. In this work, we describe the chemical synthesis of branched α-Gal-containing pentasaccharides with terminal, non-reducing α-Gal residues. The target pentasaccharides were conjugated to Bovine Serum Albumin (BSA), which produced neoglycoprotein antigens for testing in serological assays. This work could potentially lead to the discovery of novel biomarkers and glycovaccine(s) for Chagas disease.

Synthesis of novel branched α-Gal-containing pentasaccharides derived from Trypanosoma cruzi tGPI-mucins

ACS Spring 2022

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