Intervention of carbohydrate recognition by proteins and nucleic acids.

Abstract

Carbohydrates in biological systems are often associated with specific recognition and signaling processes leading to important biological functions and diseases. Considerable efforts have been directed toward understanding and mimicking the recognition processes and developing effective agents to control the processes. The pace of discovery research in glycobiology and development of carbohydratebased therapeutics, however, has been relatively slow due to the lack of appropriate strategies and methods available for carbohydrate-related research. This review summarizes some of the most recent developments in the field, with particular emphasis on work from our laboratories regarding the use of chemoenzymatic strategies to tackle the carbohydrate recognition problem. Highlights include the study of selectincarbohydrate and aminoglycoside-RNA interactions and development of agents for the intervention of these recognition processes.Of the three major classes of biomolecules, carbohydrates perhaps are the least exploited. It has been known that carbohydrates can serve as structural components of natural products, as energy sources, or, more interestingly, as key elements in various molecular recognition processes, including bacterial and viral infections, cell adhesion in inflammation and metastasis, differentiation, development, regulation, and many other intercellular communication and signal transduction events (1). [Representative structures are presented in Fig. 1 (2-16).] The precise mechanism of many carbohydratemediated recognition processes are, however, not well understood, and, though potential opportunities exist, the pace of development of carbohydrate-based pharmaceuticals has been slower than that of the other classes of biomolecules. Several reasons may be attributed to this slow pace of development. First, some technical problems in the field are impossible or difficult to solve. There is no PCR equivalent replication system available for the amplification of minute amounts of carbohydrates to facilitate structure analysis and synthesis, and there is no machine available for the solid-phase synthesis of oligosaccharides to facilitate the study of their functions. In addition, synthesis of oligosaccharides in large quantities for therapeutic evaluation and development is in general very difficult and expensive. Second, carbohydrates generally possess undesirable properties for drug development. The affinity of carbohydrates for their protein receptors is relatively weak (17-21), with dissociation constants in the millimolar range, and carbohydrates are generally orally inactive and sensitive to enzymes in vivo. As a result, carbohydrates may only be used as injectable form for the treatment of acute symptoms.Understanding carbohydrate recognition is important, however, as this recognition process often occurs at the early stage of disease development, and intervention of such process may be beneficial. Furthermore, understanding the mechanism of carbohydrate recognition may lead to the devel...

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