Cell-permeable inhibitors for new classes of enzymes are described in a paper published online this week in Nature Chemical Biology. These enzyme inhibitors have relevance for exploring the basic biology behind diseases by understanding development, cell trafficking, and host-pathogen interactions.
Finding enzyme inhibitors that can cross the cell membrane to act in cells remains a significant challenge, especially for inhibitors of carbohydrate processing enzymes that are often highly charged. The cellular enzymes that control carbohydrate metabolism are known to permit some non-natural molecules into normal metabolic pathways. In addition, medicinal chemists have long worked on ‘pro-drugs’, or molecules that are disguised in some way and then altered once inside the body or a cell to become active. Prior research had demonstrated that these two ideas could be combined to create a sugar analogue that is disguised to allow cell permeability, but then gets transformed in several steps into an activate inhibitor of a glycosyltransferase.
James Paulson and colleagues demonstrate that this same strategy can be used to create synthetic inhibitors of sialyltransferases and fucosyltransferases, enzymes that attach special sugar groups - sialic acids and fucoses, respectively - to a variety of biological targets. As there are currently no small molecule inhibitors of these enzymes that work in cells, these new compounds should provide immediate entry to further research into how carbohydrate structure is linked to important biological processes.