Sugar-mimic glycosidase inhibitors: natural occurrence, biological activity and prospects for therapeutic application

Alkaloids mimicking the structures of monosaccharides are now believed to b e widespread in plants and microorganisms, and these sugar mimics inhibit g lycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Naturally occurring sugar mimics with a nitrogen in the ring are classified into five structural classes: polyhydroxylated piperidi nes, pyrrolidines, indolizidines, pyrrolizidines and nortropanes. Glycosida ses are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and t he lysosomal catabolism of glycoconjugates. The realization that alkaloidal sugar mimics might have enormous therapeutic potential in many diseases su ch as viral infection, cancer and diabetes has led to increasing interest a nd demand for these compounds. Most of these effects can be shown to result from the direct or indirect inhibition of glycosidases. The glycosphingoli pid (GSL) storage diseases are relatively rare hereditary disorders that ar e severe in nature and frequently fatal. Possible strategies for the treatm ent of these lysosomal storage diseases include enzyme replacement therapy, gene therapy and substrate deprivation. Recently, quite a new therapy for lysosomal storage diseases has been reported, namely a 'chemical chaperone therapy' for Fabry disease. In this report, the structural basis for the sp ecificity of inhibition of alkaloidal sugar mimics and their current and po tential application to biomedical problems will be reviewed. (C) 2000 Elsev ier Science Ltd. All rights reserved.