By: Richard D. Cummings
Automated synthesis of glycans (oligosaccharides and polysaccharides) has been a major goal of glycoscience for many years (1-3). Such materials can be used in vaccines, as for bacterial polysaccharides, and in an industrial and biological context, as for synthesis of glycans of glycoproteins and glycolipids. As a prelude in this quest, it is important to recognize that Bruce Merrifield won the 1984 Nobel Prize in Chemistry for solid-phase synthesis of proteins (4), and Gobind Khorana had earlier won the 1968 Nobel Prize in Physiology or Medicine for synthesis of oligonucleotides (5). These advancements led the way to potential solid-phase approaches for glycan synthesis. Recently there have been key advancements in this area of automated building block and glycan synthesis (2, 3, 6-18). A few examples are discussed here.
Seeberger’s group first generated by solid-phase automated synthesis a branched dodecasaccharide using glycosyl phosphate building blocks and an octenediol functionalized resin (1). More recent studies from that group expanded automated synthesis from relatively small oligosaccharides to a 151-mer polysaccharide (19). Ye’s group has synthesized a mycobacterial arabinogalactan containing 92 monosaccharide units (20). Recently, a set of fucoidan oligosaccharides (a fucose-containing polysaccharide in algae) with up to 20 cis-glycosidic linkages, diverse branching patterns, and 11 sulfate monoesters was also described (21). Another recent report described the total synthesis by automated approaches of remarkable branched arabinogalactans containing up to 140 monosaccharide residues (22). Another remarkable example of what should more accurately be termed ‘semi-automated’ synthesis was described by Ye’s group for a polysaccharide (arabinan) composed of 1,080 monosaccharides (arabinose) which has 4,320 stereogenic centers and a size of 352,700 Daltons (23). This appears to be the largest polysaccharide chemically synthesized to date. While these are linear molecules, ultra-large cyclic polysaccharides have also been synthesized by Nokami’s group, some containing up to 17 mannose residues (14).
What does the future hold for automated synthesis of glycans? There are some key hurdles to address, namely the problem of intermediates for assembly of glycans, protecting group addition and removal, anomeric configuration of products, and other issues. Another problem is, of course, the vast diversity of glycans, the vast numbers of glycan modifications, e.g., sulfation, acetylation, phosphorylation, which govern molecular interactions. Some of these hurdles may be solved using automated chemoenzymatic strategies (24). Thus, the future is incredibly bright, as researchers are developing approaches to overcome each of these obstacles. The day will likely come when commercial sources of glycans can be made on demand, and perhaps even libraries of related materials for structure/function studies. Often, only relatively small amounts of materials are needed for screening and biological assays, and such screening can identify targets to generate in larger quantities. Thus, there is a clear need of methods for small-scale and large-scale synthesis of glycans.
References
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