Automated Synthesis of Oligosaccharides

Automated Synthesis of Oligosaccharides

Oligosaccharides are one of the most important classes of biomolecules. They are involved in a variety of biochemical processes, such as cell differentiation, proliferation and adhesion, inflammation and immune responses. However, it is often difficult or even impossible to isolate this carbohydrate structures from natural sources. Chemical synthesis is a powerful tool in order to furnish sufficient amounts of pure oligosaccharides for biological evaluation or vaccine production. However, the classical solution phase synthesis of oligosaccharides is often a time-consuming task and usually requires a special strategy for each molecule.

To overcome these problems solid phase synthesis is a powerful alternative approach. This approach leads to carbohydrate structures of interest, that could be further used for the synthesis of glycoconjugates or glyco-arrays. The repetitive character of solid-supported oligosaccharide synthesis makes this process suitable for automation like in peptide or oligonucleotide synthesis. The first syntheses were performed successfully in a modified ABI peptide synthesizer, which features were adapted for carbohydrate chemistry.[1] With the help of this setup it was shown that automated synthesis reduces the expenditure of time dramatically[2] and an anti-malaria toxin was already obtained which is expected to enter clinical trials in 2011.[3]

To meet the specific requirements of carbohydrate synthesis properly, a fully automated carbohydrate synthesizer was developed.[4] In combination with the design and use of a versatile linker a-1,6-linked glucosamine oligosaccharides, a Sialyl Lewis X tetrasaccharide or the common core pentasaccharide structure of N-glycans were obtained and thus, it was shown, that the automated oligosaccharide synthesizer can be used to obtain complex and biologically relevant carbohydrate structures. This concept is now transferred to the automated synthesis of glycosaminoglycans that are linear oligosaccharides containing a disaccharide repeating unit with different sulfation patterns. Due to this fact, their synthesis belongs to one of the greatest challenges for carbohydrate chemists. In order to avoid many solution synthesis steps after the assembly of the oligosaccharide chain, sulfation and partial deprotection steps should be carried out on solid support. This leads to a high demand on linker and building blocks for the automated synthesis of glycosaminoglycans.



[1] Plate, O. J., Palmacci, E. R., Seeberger, P. H.: Automated Solid Phase Synthesis of Oligosaccha-rides. Science 291, 1523–1527 (2001).

[2] Love, K. R., Seeberger, P. H.: Automated Solid Phase Synthesis of Protected Tumor-Associated Antigen and Blood Group Determinant Oligosaccha-rides. Angew. Chem. Int. Ed. 43, 602–605 (2004).

[3] Schofield, L., Hewitt, M. C., Evans, K., Siomos, M. A., Seeberger, P. H.: Synthetic GPI as a Candidate Anti-toxic Vaccine in a Model of Malaria. Nature 418, 785–789 (2002).

[4] Seeberger, P. H.; Kröck, L.; Esposito, D.; Wang, C.-C; Castagner, B; Bindschädler, P.: Fully Automated Solid-Phase Oligosaccharide Synthesis to Access Glycan Microarrays and Conjugate Vaccines; manuscript in preparation.

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