Recent advances in the synthesis of α-dystroglycan O-mannose glycans

Abstract

α-Dystroglycan (α-DG) is an important component of the extracellular domain of the dystrophin complex, with extensive and diverse O-mannosylation modifications, which can widely participate in various physiological and pathological processes. In particular, core M1, core M2, and core M3 O-mannose glycans, which are post-translational modifications of α-DG, are shown to play critical roles in muscle and brain development. However, elucidating their precise mechanisms has been hampered by inherent structural heterogeneity, creating an urgent demand for efficient methods to obtain homogeneous glycans. Despite their structural complexity, tremendous progress has been made in the synthesis of O-mannose glycans and glycopeptides in recent years. By systematically comparing synthetic strategies and methodologies, this review highlights recent progress in the chemical, enzymatic, and chemoenzymatic synthesis of the three major O-mannose glycan types of α-DG. In addition, key synthetic challenges, including stereoselective glycosylation, site-specific functionalization, and scalability, are discussed. Finally, current limitations and future perspectives in O-mannose glycans synthesis are outlined, aiming to inspire further methodological innovation and biological applications.