Type I α-1,2-mannosidase (MAN I) enzymes have been described as promising targets for the treatment of cancer, viral infections,  sarcoglycanopathies,  lysosomal storage disorders, and for the preparation of therapeutic high mannose bearing glycoproteins. Despite the therapeutic potential of inhibiting MAN I enzymes, little progress has been made in the development of inhibitors. Kifunensine, an alkaloid isolated in the 1980’s from the actinomycete Kitasatosporia kifunensine no. 9482, remains the predominant MAN I inhibitor. Efforts to identify kifunensine analogues or novel scaffolds with enhanced activity have yet to provide an inhibitor with superior activity in cellular assays. The development of cell-based assays to aid the discovery and development of MAN I inhibitors is significantly hampered by the scarcity of tools available to specifically detect glycocalyx localized high mannose N-glycans induced by MAN I inhibitors. Here we will describe our efforts to fill this void with the design and preparation of lectin-based tools that can detect high mannose N-glycans on cell surfaces. Importantly, these lectin constructs can be applied to assess changes in cell surface glycosylation induced by type I but not type II mannosidase inhibitors. These tools have facilitated our efforts to development of MAN I inhibitors, and have importantly led us to identify kifunensine analogues that are &gt;75-fold more potent than kifunensine.

A functionalized high mannose-specific lectin for the discovery of potent type I mannosidase inhibitors

ACS Spring Meeting 2021

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