Chapter 31. Carbohydrates as Drug Discovery Leads

Abstract

Publisher Summary Of all the biopolymeric structural types, carbohydrates have the greatest theoretical potential for specificity and new lead generation. Research on carbohydrates is now undergoing considerable growth and promises to be a major focus as drug discovery leads. X-ray crystallographic data are providing insight into the atomic features of protein–carbohydrate interactions. Computer-aided modeling of oligosaccharides employing molecular dynamics simulations is providing useful tools for the study of carbohydrate structure. Progress is being made in the synthesis of biologically active glycopeptides and glycolipids as a result of the developments in glycosylation methods and protective group strategies. Many carbohydrates of current interest are expressed glycoconjugates on the cell surface. They can be classified as glycolipids, glycoproteins, or proteoglycans. With respect to regulatory and proprietary issues, protein glycoforms are becoming a part of the strategy for patent applications and drug development. Glycosyl ransferases and glycosidases modulate the biosynthesis of cell–surface complex carbohydrates and have a considerable effect on both the biophysical and biochemical actions of glycoconjugates. Carbohydrate groups provide signals for protein targeting and cell–cell interactions and serve as receptors for binding toxins, viruses, and hormones. They control vital events in fertilization and early development, regulate many critical immune system recognition events, and target aging cells for destruction. Carbohydrates are critical in the initiation of bacterial and viral infections. There is strong evidence that specific cell-surface carbohydrates expressed on colonic, pancreatic, and other tumors are involved in metastasis. Carbohydrates can also alter drug pharmacokinetics and efficacy. Taken together, the knowledge of carbohydrate synthesis, structure, and function can serve the medicinal chemist well in the design of new drug candidates.