Antidiabetic plants and their active constituents.

Alkaloids mimicking the structures of monosaccharides are now believed to be widespread in plants and microorganisms, and these sugar mimics inhibit glycosidases 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 piperidines, pyrrolidines, indolizidines, pyrrolizidines and nortropanes. Glycosidases are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The realization that alkaloidal sugar mimics might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes has led to increasing interest and demand for these compounds. Most of these effects can be shown to result from the direct or indirect inhibition of glycosidases. The glycosphingolipid (GSL) storage diseases are relatively rare hereditary disorders that are severe in nature and frequently fatal. Possible strategies for the treatment 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 specificity of inhibition of alkaloidal sugar mimics and their current and potential application to biomedical problems will be reviewed.

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

Polyhydroxylated alkaloids -- natural occurrence and therapeutic applications.

α- and β-Glucosidase inhibitors: chemical structure and biological activity

Increased understanding of the role of protein- and lipid-linked carbohydrates in a wide range of biological processes has led to interest in drugs that target the enzymes involved in glycosylation. But given the importance of carbohydrates in fundamental cellular processes such as protein folding, therapeutic strategies that modulate, rather than ablate, the activity of enzymes involved in glycosylation are likely to be a necessity. Two such approaches that use imino sugars to affect glycosylation enzymes now show considerable promise in the treatment of viral infections, such as hepatitis B, and glucosphingolipid storage disorders, such as Gaucher disease.

Targeting glycosylation as a therapeutic approach

Antiretroviral activity of castanospermine and deoxynojirimycin, specific inhibitors of glycoprotein processing

α-Homonojirimycin [2,6-dideoxy-2,6-imino-d-glycero-l-gulo-heptitol] from omphalea diandra L.: isolation and glucosidase inhibtion

MDL 25,637 is a novel compound designed as a transition-state inhibitor of alpha-glucohydrolases. This compound inhibits rat intestinal sucrase, maltase, isomaltase, glucoamylase and trehalase activities at micromolar concentrations. It is a much weaker inhibitor of alpha-amylase and lactase. Inhibition of sucrase was competitive with sucrose. In mice, MDL 25,637 inhibited the rise in serum glucose after a sucrose or starch load but not after a glucose load. MDL 25,637 also reduced the glycemic response to sucrose in rats. The drug was most effective when administered 0 to 30 min before the sucrose load and was as effective in streptozotocin-treated rats as in normals. The inhibition by MDL 25,637 of intestinal glucohydrolases is an effective means of reducing the hyperglycemic response to an oral sucrose or starch load and, as such, warrants further investigation as a potential drug for the treatment of diabetes mellitus.

Paul S. Liu

Papers

Antiretroviral activity of castanospermine and deoxynojirimycin, specific inhibitors of glycoprotein processing

α-Homonojirimycin [2,6-dideoxy-2,6-imino-d-glycero-l-gulo-heptitol] from omphalea diandra L.: isolation and glucosidase inhibtion

Inhibition of intestinal disaccharidases and suppression of blood glucose by a new alpha-glucohydrolase inhibitor--MDL 25,637.

Castanospermine blocks the hyperglycemic response to carbohydrates in vivo: a result of intestinal disaccharidase inhibition.

A potent inhibitor of β-N-acetylglucosaminidases: 6-acetamido-6-deoxycastanospermine