 |
| About Bioline | All Journals | Testimonials | Membership | News |
|
||||||
|
||||||
Australasian Biotechnology, Vol. 12, No. 3, June-July, 2002, pp. 35-37 CARBOHYDRATES AS MEDICINES GLYCOSCIENCE: OLIGOSACCHARIDES AS DRUGS, FUNCTIONAL FOODS, AND RECEPTORS IN THE GUT Martin J Playne Melbourne Biotechnology, 1 Lorraine St., Hampton, Victoria, 3188. Email: mplayne@netspace.net.au Code Number: au02021 Abstract The emerging use of specific oligosaccharides for the development of new drugs and new functional prebiotic foods is reviewed. One important gut function is to act as alternative receptors for bacterial lectins. Their presence on mucosal gut surfaces results in modification of normal patterns of bacterial adhesion to mucosal epithelial surfaces, and thus prevents the establishment in the gut of infectious disease organisms. They are also being developed as novel glycotherapeutics for cancer cardiovascular diseases, diabetes, obesity and wound healing, and for immunomodulation, as well as for use in infant milk formula This paper lists the main commercial developments world-wide by specialist glycoscience companies to date, and provides a listing of such companies. Information is also provided on companies offering custom analytical services for oligosaccharides and glycosylated products, and of those supplying specific oligosaccharides and related products to researchers and drug development companies. Introduction Drugs utilising the structural and functional properties of carbohydrates are increasing in the marketplace, and there are a pipeline of such drugs under development. Since 1990, there has been a recognition that we are entering the age of glycobiology or glycoscience. However, this discipline has been slow to take off, despite big advances in analytical chemistry of carbohydrates, which are essential for the field to make progress. A number of firms were spawned in the early 90's (eg., Biocarb, Oxford Glyco Sciences, Synsorb, Neose, Glycomed, Greenwich Pharmaceuticals, Enzon, Cytel). Not all of these survive today. In Australia, we have seen two glycoscience companies form: Alchemia in Brisbane (part of the Medica group), which was formed in 1995, and Megazyme whose primary business is carbohydrate analytical kits. Megazyme subsequently re-located to bclaiid in 1996, but retains a strong Australian connection through its expertise in cereal chemistry. Most of these small high-tech 'discovery' companies were formed as a result of 'spin-offs' from university departments or research organisations. In common with many biotech companies, they retain strong research links with academia, and have developed strong commercial links or joint ventures with major multinational pharmaceutical companies. This paper provides a comprehensive list of such R&D companies, many of which have also synthesized a range of carbohydrates for sale and some also offer analytical services, as well as having their longer-term aim of developing new carbohydrate drugs. However, there are other companies not listed here, like Progen Ltd (Brisbane), whose lead drug P188, which is under phase 2 clinical trials, is derived from phosphomannan. Progen, however, did not develop by the same route as the glycoscience companies listed in this article. A number of university departments, with carbohydrate expertise, also provide analytical services and research collaborations. Why oligosaccharides? Glycans with nucleic acids and proteins are widely distributed in living organisms. All of these polymers are covalently linked, but glycans have characteristics not found in other two. Notably the nature of the linkage between monomeric units in glycans is much more variable than that found in the other polymers, and this leads to a much greater variety in the sequence of the bioploymer. Thus, this leads to a huge structural diversity of oligosaccharides in glycosylated compounds (glycoproteins, glycolipids). The number of combinations of structural linkage between monomers is high. For example, a galactose unit can be linked to a mannose unit in four positions (C2, C3, C4 and C6), and thus form four isomeric structures. Additionally, a galactose moiety can take two anomeric configurations, meaning that the number of combinations rises to eight. Furthermore, a galactose moiety can occur in both furanose form and pyranose form, thus 16 possible isomeric structures occur with this Gal-Man disaccharide. As the number of linkages expand, so do the seemingly endless possible combinations. In contrast to proteins and nucleic acids, glycans are not constrained by limitations on molecular structure, as they can branch when more space is needed. Neither are glycans constrained by genetic templates as is the case with nucleic acids and proteins (Kobata, 1993). This structural diversity (and flexibility) has led to the emerging science of glycobiology and its applications in medicine in the development of targeted drugs (Rademacher etal 1988). Functional foods In the functional food sector, the emphasis is on the use of cheaper, less pure, food-grade oligosaccharide mixtures (and other carbohydrates) as prebiotics, aimed at modulating gut microflora and gut metabolism. However, in considering these, we do have to be aware of the studies and advances that are occurring in the medical applications of specific oligosaccharides, as outlined in this paper. For example, treatment of gut infectious diseases has been proposed from such work. There is also work on the ability of specific oligosaccharides to bind to gut mucosal and epithelial surfaces and thus prevent attachment of certain microorganisms. Such findings obviously have implications as to the modes of action of food-grade oligosaccharides. Food-grade oligosaccharides differ from those of glycobiology in that they are impure products, containing residual feedstock carbohydrate and monomer sugars, as well as a range of types of oligosaccharides. Prices as food ingredients are kept competitive by utilisation of simpler manufacturing methods, and avoidance of expensive purification steps. Food grade non-digestible oligosaccharides are prepared by several methods. Some are extracted from plant materials and used directly, e.g., tnulin, some resistant starches, soybean and many dietary fibres. Others are modified enzymically after extraction of the crude parent feedstock from plants (eg., xyloand some fructoYet others are synthesized from simpler molecules (eg., galacto-oligosaccharides from lactose), or transformed from such molecules (eg., lactitol and lactulose from lactose) (Playne & Crittenden 1996; Crittenden & Playne, 1996) Drugs In pharmaceutical applications, where specific structures of pure compounds are needed, synthesis of the oligosaccharide is far more complex and expensive, requiring complex enzymic syntheses by glycosyl transferases. Use of glycosyltransferases of the Leloir pathway provides the necessary specificity and purity, and can overcome problems found with chemical synthesis of specific oligosaccharides. However, it requires sugar nucleotides and glycosyl transferases, both of which have not been readily available (at least, not cost-effectively). (For more detail, see Koizumi etal., 1998; Nilsson, 1988; Rastall and Bucke, 1992). Some examples The term 'chemical probiosis' has been coined by workers at the Rowett Research Institute to mean the ability of specific oligosaccharides found in human milk and colostrum to block the adhesion of K88 E.coli. A Canadian company, Synsorb Biotech Inc has developed an oligosaccharide ('Synsorb') with an inert carrier, which acts as an alternative receptor to absorb lectin-like toxins from toxigenic bacteria (VTEC, ETEC, Cl dijficile). Zopf and Roth (1996) discussed the use of oligosaccharides as anti-infective agents, using a decoy oligosaccharide in the mucous layer to bind the microorganism's carbohydrate binding proteins. They claim that such oligosaccharides (as found in human milk) prevent pathogens attaching. An example is given of the Neose technologies anti-Helicobacter pylon oligosaccharide, NE 0080. Idota (1994) has examined the utilisation by bifidobacteria and by lactobacilli of certain human milk oligosaccharides. Sialyl lactose was only used by B. infantis, whereas N acetyl iieuraminlc acid was used by B. longum, L. casei, and L. salivanius but not by L. acidophilus. Human milk contains 3 to 6 g/L of oligosaccharide (Kunz and Radloff, 1996 ), but cow's milk contains very little (0.03-0.06g/L) and most of that is sialyl lactose. The major oligosaccharides in human milk are lacto-N-tetraose and lacto-NKunz and Radloff regard the evidence as strong that these compounds are potent inhibitors of bacterial adhesion to mucosal surfaces and epithileal cells.. Kunz and Radloff state: "Human oligosaccharides are considered to be soluble receptor analogues of epithelial cell surfaces, participating in the non-immunological defence system of human milk-fed infants". Thus, there is growing industrial interest in including certain oligosaccharides in infant milk formula. Glycoscience Network A useful internet site is www.vei.co.uk/TGN/ This site hosts a Glycoscience Interest Group (GIG), and a newsgroup (bionet.glycosci) The site also links to (i) information resources, (ii) academic links, and (iii) commercial links. It is being maintained, and provides a good starting point for information in this area. See also www.ispex.ca/companies/glycobiology/, www.informagen.com, and www.prnewswire.com/cnoc/ for listings and background of companies. Glycoscience Companies A list of companies involved in the development of carbohydrate drugs, in the synthesis and supply of specific oligosaccharides and their analysis is given in Table 1. This table is designed to provide the reader with information on how to find particular specialty carbohydrate products. Listings of this type, by their very nature, become dated quickly, and are never comprehensive. Spin-offs from academic departments are continually occurring, and readers are advised to also contact appropriate academic units in universities and CSIRO to ascertain if they can supply products and services in this specialised area. In Table 1, commercial groups in three areas are listed with their contact details and websites. The three areas are:
PHARMACEUTICALS - Developers of specific oligosaccharides as drugs References
About the author: I)r Martin Playne is Director of Melbourne Biotechnology, which is a consulting and research business, specialising in pro biotic bacteria and prebiotic carbohydrate ingredients and their applications and efficacy in functional health foods. Dr Playne is an Adjunct Professor in the Faculty of Life Sciences at RMIT University. He is also Editor of this journal. Copyright 2002 - AusBiotech Ltd. |
| |||||||||
