An enzyme inhibitor is created from an inactive molecule by manipulating normal cellular machinery, in a study online in Nature Chemical Biology this week. This strategy could enable new exploration of the biological role of carbohydrate modifications, with relevance for diseases such as diabetes, inflammation, and cancer.
Creating enzyme inhibitors that can cross the cell membrane and act in cells remains a significant challenge, especially for the highly-charged inhibitors typical of carbohydrate-modifying enzymes. ?The cellular enzymes that control carbohydrate metabolism are known to permit some non-natural molecules into normal metabolic pathways; indeed, this pathway has famously been used as a research tool to insert sugars into cell surfaces for fluorescent labeling. In addition, medicinal chemists are familiar with the idea of ‘pro-drugs’, or molecules that are disguised in some way and then altered once inside the body or a cell to become active.
David Vocadlo and colleagues combine these ideas to create a sugar analogue that is disguised to allow cell permeability, but can then transform into an activated molecule inside mammalian cell lines. This active compound is an effective inhibitor of one of the most important carbohydrate processing enzymes, but surprisingly, inhibiting this enzyme has little impact on the growth of the cells.