Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Canada.
Org Biomol Chem. 2012 Oct 3;10(41):8348-60. doi: 10.1039/c2ob26355f.
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 β-mannan component is attached to the branches either via a glycosidic bond (acid stable β-mannan) or a phosphodiester bond (acid-labile β-mannan). The α-mannan residues of the cell wall phosphomannan do not afford protective antibody, while the β-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 β1,2-mannopyranosyl trisaccharide linked via a phosphodiester to methyl α-mannopyranoside. This encompasses the attachment site of the acid labile β-mannan to the α-mannan component of the cell wall phosphomannan. The trisaccharide was formed by an iterative process to first create a β-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 β-mannotrioside in hapten inhibition experiments. The observed activities are rationalized with a model for docked in the binding site of C3.1.
念珠菌属的细胞壁磷酸甘露聚糖是一种复杂的 N-连接糖蛋白，其聚糖链主要含有α-连接的甘露糖主链和α-甘露糖支链。少量的β-甘露聚糖部分通过糖苷键（酸稳定的β-甘露聚糖）或磷酸二酯键（酸不稳定的β-甘露聚糖）连接到支链上。细胞壁磷酸甘露聚糖的α-甘露糖残基不能提供保护性抗体，而β-甘露聚糖部分是一种保护性抗原，已成为缀合疫苗的关键表位，成为有吸引力的目标。我们首次合成了四糖 1，它由通过磷酸二酯键连接到甲基 α-甘露吡喃糖苷的β1,2-甘露吡喃糖基三糖组成。这包括酸不稳定的β-甘露聚糖与细胞壁磷酸甘露聚糖的α-甘露聚糖部分的连接点。三糖是通过一个迭代过程形成的，首先形成β-吡喃葡萄糖苷键，然后通过氧化还原序列将 C-2 中心差向异构化。磷酸二酯键是通过糖的 H-膦酸酯连接得到的。已经评估了磷酸甘露聚糖片段 1 与保护性抗体 C3.1 的结合，并与半抗原抑制实验中的β-甘露三糖苷进行了比较。观察到的活性与 C3.1 结合位点中对接模型进行了合理化。
