Synthesis of a Candida albicans tetrasaccharide spanning the β1,2-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 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.

Synthetically prepared glycooligosaccharides mimickingCandida albicanscell wall glycan antigens - novel tools to study host-pathogen interactions

“…The oligosaccharidic moiety of these conjugates is branched (M5‐1, M5‐2 and M6) or highly substituted (M7‐A), contrary to the M2 and M7‐B structures. Such Ig class engagement can be ascribed to the oligosaccharide structure–immunobiological efficacy interrelationships (Han et al ., ; Cutler et al ., ; Dang et al ., ; Paulovičová et al ., ). Moreover, the antibody isotype and subclass may strongly influence the specificity and the antifungal protective capacity of certain antisaccharide antibodies (Torres & Casadevall, ).…”

“…The immunobiological importance of oligosaccharidic chains of fungal cell wall carbohydrates, particularly serological specificity and the relationship between biological activity and structure (Fukazawa et al ., ; Suzuki, ; Shibata et al ., , ), stimulated the development of a stereospecific synthesis of related oligosaccharides. A variety of synthetic linear and branched manno‐ and glucooligosaccharides that represent fungal cell wall mannan and glucan antigenic structures were prepared (Karelin et al ., , , ; Collot et al ., ; Bromuro et al ., ; Costello & Bundle, ; Dang et al ., ; Tanaka et al ., ; Yashunsky et al ., ) and proposed as molecular probes to study host–fungal interrelationships and recognition by immunocompetent cells (Dromer et al ., ; Dalle et al ., ; Standaert‐Vitse et al ., ; Vandewalle‐El Khoury et al ., ; Paulovičová et al ., , ) and also for diagnostic purposes and vaccine development (Xin et al ., , ; Bromuro et al ., ; Adamo et al ., ). The incorporation of glycans, or their protein‐conjugated fragments, into the anti‐ Candida vaccine formulation represents a new trend in the research and development of subcellular prophylactic or therapeutic anti‐ Candida vaccine.…”

Importance of Candida Antigenic Factors: Structure-Driven Immunomodulation Properties of Synthetically Prepared Mannooligosaccharides in RAW264.7 Macrophages

“…The immunobiological importance and vaccination potency of synthetically prepared β-1,2-mannopyranosyl trisaccharide mimicking the structure of the C. albicans cell surface epitope has previously been studied (Xin et al, 2008, 2012; Costello and Bundle, 2012; Cartmell et al, 2015; Bundle et al, 2018). Next, a novel tetrasaccharide construct consisting of β-1,2-mannopyranosyl trisaccharide and α-mannopyranoside was designed and suggested as a model of the C. albicans phosphodiester epitope (Dang et al, 2012). Glycoarrays formed by biotinylated oligosaccharides loaded on streptavidin-coated surfaces were previously shown to be indispensable instruments for the investigation of carbohydrate antigen recognition by immune cells (Komarova et al, 2015, 2018; Akhmatova et al, 2016; Paulovicova et al, 2016, 2017; Kurbatova et al, 2017; Argunov et al, 2019; Schubert et al, 2019).…”

Acetylated Trivalent Mannobioses: Chemical Modification, Structural Elucidation, and Biological Evaluation

“…[25,26] Another popular method is based on the use of ag lucosyl donor with ad irecting group, such as an ester functionality,o nC 2t op repare a1 ,2-trans-glycoside followed by epimerization of the C2 atom to finally yield the target b-mannoside. [27,28] Based on our previous experience,w er elied on the Crich b-mannosylation protocol, [29] by which am annose thioglycosidei sc onvertedi nto an a-triflate, which then subsequently undergoes an S N 2-like addition of the alcohol to afford the b-mannoside. This method, althoughi nvolvingaslightly complex activation protocol, benefits from being at wo-step one-pot reaction and the fact that preparing the donor only requires onea dditional synthetic step.…”