Synthesis of a multivalent α-1,2-mannobiose ligand for targeting C-type lectins†

Abstract

The importance of lectins in biological processes such as pathogen recognition, cell adhesion, and cell recognition is well documented. C-Type lectins, which require calcium for binding, play an important role in the innate immune response by engaging carbohydrates presented as part of the human and pathogen glycocalyx. For example, lectins such as MBL, Dectin-2, langerin and DC-SIGN selectively recognize mannose rich (high-mannose) structures presented as part of the glycocalyx. One common sugar binding motif that is recognized by these lectins on the pathogen glycocalyx is α-1,2-mannobiose, a disaccharide that consists of two mannose units connected via a α-1,2-linkage. To study the binding of these motifs in different contexts, synthetic replicas of α-1,2-mannobiose that can be presented in a multivalent fashion mimicking their presentation on the glycocalyx are required. Here we present the synthesis of a novel α-1,2-mannobiose analog bearing an azido linker from known precursors using a split and combine approach guided by neighboring group participation. Our approach makes it possible to achieve comparatively high yields and stereoselectivities while reducing the number of steps required to prepare such structures. We also introduce, for the first time, the trivalent presentation of our α-1,2-mannobiose ligand on a precision glycomacromolecule using copper-catalyzed azide–alkyne cycloaddition (CuAAC) to create high-mannose mimetics. Such structures have the potential to serve as probes for unlocking the rules of engagement between high-mannose glycans and C-type lectins like langerin and DC-SIGN.