Synthesis of a Candida albicans tetrasaccharide spanning the ß1,2-mannan phosphodiester α-mannan junction.

ABSTRACT

The cell wall phosphomannan of Candida species is a complex N-linked glycoprotein with a glycan chain containing predominantly an α-linked mannose backbone with α-mannose branches. A minor ß-mannan component is attached to the branches either via a glycosidic bond (acid stable ß-mannan) or a phosphodiester bond (acid-labile ß-mannan). The α-mannan residues of the cell wall phosphomannan do not afford protective antibody, while the ß-mannan portion is a protective antigen and has become an attractive target as the key epitope of a conjugate vaccine. We report the first synthesis of a tetrasaccharide 1 consisting of a ß1,2-mannopyranosyl trisaccharide linked via a phosphodiester to methyl α-mannopyranoside. This encompasses the attachment site of the acid labile ß-mannan to the α-mannan component of the cell wall phosphomannan. The trisaccharide was formed by an iterative process to first create a ß-glucopyranoside linkage and then epimerize the C-2 center via an oxidation-reduction sequence. The phosphate diester linkage was accessed via an anomeric H-phosphonate. The binding of phosphomannan fragment 1 with the protective antibody C3.1 has been evaluated and compared with a ß-mannotrioside in hapten inhibition experiments. The observed activities are rationalized with a model for docked in the binding site of C3.1.