Mannosidase Enzymes as Therapeutic Targets

11:00 a.m.

Zoom

Mark Farrell (Assistant Professor of Medicinal Chemistry, School of Pharmacy, University of Kansas)

Cellular glycosylation is an important and highly regulated process. The resulting glycoconjugates modulate and mediate a wide variety of functions in physiological and pathophysiological states. Genetic defects in glycosylation are often embryonic lethal, underlying the vital roles of glycans. However, in many disease states cellular glycosylation becomes dysregulated and aberrant glycosylation ensues.

Alterations in glycosylation patterns are among the first biomarkers of cancer. Glycosylation changes include an increase in sialyl Lewis structures, fucosylation, and the branching of N-glycans. N-glycans are a class of oligosaccharides that are prevalent on cell surface localized proteins that play important roles in cellular processes. The N-glycans on these proteins facilitate protein localization and there are numerous examples demonstrating that the aberrant N-glycosylation of these proteins facilitates malignancy progression. As such, manipulating N-glycosylation in diseased cells holds the potential to disrupt disease progression.

Mannosidase enzymes are integral to the processing of N-glycans but to date the potential of these enzymes as therapeutic targets for cancer therapy has yet to be fully investigated. The inhibition of these enzymes leads to the increased expression of high mannose N-glycans, which are not typically prevalent on the surfaces of healthy, but are recognized by the immune system. Here we will describe the preparation of tools to detect high mannose N-glycans, the development of mannosidase inhibitors, and our studies to use mannosidase inhibitors sensitize B cell malignancies to immunotherapies.