Chemoenzymatic Synthesis of Sialosides and Sialidase Inhibitors

Released on by Zahra Khedri
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  • Chemoenzymatic Synthesis of Sialosides and Sialidase Inhibitors Book Detail

  • Author : Zahra Khedri
  • Release Date : 2012
  • Publisher :
  • Genre :
  • Pages :
  • ISBN 13 : 9781267657626
  • File Size : 98,98 MB
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Chemoenzymatic Synthesis of Sialosides and Sialidase Inhibitors by Zahra Khedri PDF Summary

Book Description: Carbohydrates and glycoconjugates play important functions in a variety of biological processes including growth, development, infection, immune response, metastasis, cell adhesion, and signal transduction events. Sialic acids are a diverse family of naturally occuring polyhydroxyketoaldonic acids with a nine-carbon backbone. More than fifty sialic acid structures with various modifications such as acetylation, methylation, and lactylation have been found in nature. Sialic acids are located at the terminal position of the cell surface glycoproteins and glycolipids in all vertebrates and involved in a number of biological processes. The availability of these complex compounds through synthesis will provide insight into their biological functions and might lead to discovery of new generation therapeutic agents. The application of enzymes for the synthesis of carbohydrates has some advantages over chemical methods. For example they have high stereo- and regioselectivity. Because of the mild reaction conditions (temperature, pH, and aqueous solution), protection and deprotection is reduced to minimum. However, using chemo-enzymatic synthesis which combines the flexibility of the chemical synthesis and stereo- and regioselectivity of enzymatic synthesis is considered an attractive and a practical method. Using this strategy, a highly efficient one-pot multi-enzyme method for synthesizing structurally defined sialic acid containing compounds has been developed in the Chen laboratory. We have applied this powerful method for the synthesis of two libraries of oligosaccharides containing sialic acids with non-natural modifications at different positions of sialic acids. In addition, the carbohydrate-protein interactions of these modified sialosides with bacterial and human sialidases (sialic acid hydrolyzing enzymes) were studied using a high-throughput screening method developed by our group. It was shown that the interactions are affected by the type of modifications on sialic acid and sialoside linkage to various degrees for different tested sialidases. The results obtained from the sialidase substrate specifity studies were used to design and synthesize a library of potential inhibitors against sialidases. Some of the synthesized compounds were found to be selective inhibitors of bacterial and human sialidases which provided us more information about the enzymes. The one-pot multi-enzyme chemo-enzymatic method was used for gram-scale synthesis of two important sialosides found in human milk oligosaccharides. It was shown that the enzymes (CMP-sialic acid synthetase and sialyltransferases) involved in the biosynthesis of sialosides are applicable in the large-scale production of oligosaccharides. However in order to decrease the cost of the reactions, we need to develop trans-glycosidases (transfer a sugar from an activated sugar donor to an acceptor) which utilize less expensive starting material.

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