Editorial [Hot Topic: The Medicinal Chemistry of Glycosidase Inhibitors(Guest Editors: Seiichiro Ogawa and Hideya Yuasa)]

Carbohydrates are used as nutrients, structural components and informational tags in life system and they are continuously synthesized, modified and degraded by numerous kinds of carbohydrate-related enzymes. The inhibitors of these enzymes, therefore, are commercial or potential medicines for diseases caused by upregulated or unwanted activities of these enzymes. Starch taken in the digestive system as a nutrient is degraded into glucose by amylase, maltase, etc., which is released into the blood circulatory system. In diabetics, the elevated glucose level promotes the glycation of proteins through Maillard reaction to help accumulation of advanced glycation end products (AGEs), which may fatally damage tiny blood vessels in the eyes, kidneys and so on. The inhibitors of amylase and maltase reduce blood glucose level and therefore suppress AGE accumulation. The effect of the inhibitors toward diabetes is exemplified by commercial antidiabetic drugs, acarbose (Glucobay) and voglibose (Basen). Another possible damage mechanism in diabetics includes an impaired blood stream caused by sorbitol-derived edema in cells. The elevated blood glucose level accelerates sorbitol synthesis by aldose reductase in the starting point of polyol pathway of carbohydrate metabolism, resulting in the accumulation of sorbitol in cells. In addition, fructose produced from sorbitol in the polyol pathway is more reactive toward the glycation of proteins than glucose. The aldose reductase inhibitor (epalrestat) therefore is used in symptomatic therapy of diabetes. Another potential diabetic drug is glycogen phosphorylase inhibitors, which would reduce the glucose reproduction through muscle glycogen degradation. As the outer shell of insects and crustaceans and the cell wall of Gram-positive bacteria are made of chitin and chitosan, the metabolism of these polysaccharides is a lifeline for these organisms. Thus polytoxins D, a chitin synthase inhibitor, and allosamidin, a chitinase inhibitor, are widely used as an agricultural fungicide and insecticide, respectively. On the other hand, validamycin A, a trehalase inhibitor, has antifungal activity. Trehalose is a storage carbohydrate for fungi and the trehalase inhibitor causes excess trehalose accumulation. Glycoproteins are synthesized in cells through correct folding of polypeptides and appropriate intracellular trafficking between compartments. In these biosynthetic processes, oligosaccharides are used as informative tags displaying the next actions to be conducted on the immature polypeptides or proteins. Glycoproteins with erroneously synthesized oligosaccharides are excluded from the synthetic process. Proper display of the oligosaccharides depends on timely trimming of intermediate oligosaccharides with glycosidases. Glycosidase inhibitors, such as N-butyl-1-deoxynojirimycin (NB-DNJ, Miglustat), can block the synthesis of glycoproteins required to reconstruct viruses in host cells. Therefore these inhibitors are potential antiviral agents and NB-DNJ has been subjected to clinical trials for human immunodeficiency virus (HIV). Oligosaccharides on glycoproteins can be knocked-down by a glycosyltransferase inhibitor, tunicamycin, which is used to study the functions of carbohydrates as informational tags.