The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases.

Glycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials. Two primary alternative strategies that have been pursued include pharmacological chaperones and GSL synthase inhibitors. There are theoretical advantages and disadvantages to each of these approaches. Pharmacological chaperones are specific for an individual glycoside hydrolase and for the specific mutation present, but no candidate chaperone has been demonstrated to be effective for all mutations leading to a given disorder. Synthase inhibitors target single enzymes such as glucosylceramide synthase and inhibit the formation of multiple GSLs. A glycolipid synthase inhibitor could potentially be used to treat multiple diseases, but at the risk of lowering nontargeted cellular GSLs that are important for normal health. The basis for these strategies and specific examples of compounds that have led to clinical trials is the focus of this review.