Recent advances in chemical synthesis of phosphodiester linkages found in fungal mannans

Fungal mannans are located on the exterior of the fungal cell wall, where they interact with the environment and, ultimately, the human host. Mannans play a major role in shaping the innate immune response to fungal pathogens. Understanding the phosphodiester linkage and mannosyl repeat units in the acid-labile portion of mannans is crucial for comprehending their structure/activity relationships and for development of anti-fungal vaccines and immunomodulators. The phosphodiester linkages connect the acid-stable and acid-labile portions of the mannan polymer. Phosphate groups are attached to positions 4 and/or 6 of mannosyl repeat units in the acid-stable portion and to position 1 of mannosyl repeat units in the acid-labile portion. This review focuses on the synthesis of phosphodiester linkages as an approach to the development of mannan glycomimetics, which are based on natural product fungal mannans. Development of successful synthetic strategies for the phosphodiester linkages may enable the production of mannan glycomimetics that elicit anti-fungal immune responses against existing and emerging fungal pathogens, such as Candida albicans and Candida auris.