It has been known for some time that sugars play a key role in the functioning of cells. Receptors for sugars are found on all cell walls. These compounds are known to mediate cell-to-cell exchange to participate in the immune system, and to modify proteins. They have also been found to play a role in some diseases. Despite this, however, research into and the commercial development of drugs based on glycochemicals, which are sugar-based chemicals, has been limited, due to the unavailability of these compounds.
Very few natural glycochemicals have been isolated, and unnatural sugars are either impossible - or too expensive - to produce using traditional synthetic chemistry. US company ZuChem aims to address this market need through the development of cost-effective biotransformations that are designed to produce high-purity sugars and sugar derivatives in high yields. This technology is also being applied to the low-cost production of sugars for other markets, including foods, flavours and fragrances and speciality chemicals.
Founder, president and CEO Dr David Demirjian started ZuChem in late 2001, after selling his earlier biotech venture ThermoGen to MediChem Life Sciences, which was itself later acquired by DeCode Genetics. Whilst ZuChem's longer-term goal is to develop building blocks for the pharmaceutical industry, it initially focused on identifying processes for products with existing markets in order to demonstrate the feasibility of the technology and to generate cash flow for further R&D activities.
The company estimates the global market for sorbitol, xylitol and mannitol to be about €745 million, with sorbitol accounting for 83%, xylitol 14% and mannitol 3%. Other sugars make up an additional €305 million. These sugar derivatives have applications as reduced calorie sweeteners, dental hygiene products, diabetic foodstuffs and low reactivity drug fillers.
The market for mannitol and xylitol has been held back by the lack of an economic route to them. The potential for growth could be significant if production costs can be reduced substantially. Xylitol, for example, when used in gums and toothpaste, does not lead to cavities and has even been shown to prevent them.
ZuChem's first step was to enter into a co-operative R&D agreement with the US Department of Agriculture (USDA), encompassing the rights to produce D-mannitol. Current commercial processes require pure fructose as the starting material and also make large quantities of sorbitol as a side product, thereby requiring expensive additional separation and purification steps.
The ZuChem process uses a cost-effective mixture of sugars as starting material and produces only the desired mannitol. This produces the desired sugar in very pure form, without needing any expensive refining and purification equipment.
A second generation D-mannitol bioprocess was developed using technology acquired from Hydrios Biotechnology of Finland. ZuChem is currently exploring commercialisation options for the mannitol bioprocess with a number of manufacturing partners. A biotransformation-based route to xylitol is also being developed at the USDA labs. ZuChem is investigating different processes using a variety of sugar raw materials. As with the mannitol process, only xylitol is generated.
"At this point, we have proven that we can cost-effectively produce xylitol using our biotechnology. A number of different companies have expressed interested in partnering and collaborating with ZuChem to take the process to commercialisation," says Michael J. Friesema, ZuChem's chief operating officer.
Currently ZuChem collaborates with Ingenza of Edinburgh, UK, which provides process development expertise for xylitol and other products. The company also has cooperative R&D agreements focused on developing the xylitol process that are sponsored by the Biotechnology Research & Development Corporation (BRDC), a research consortium of large companies including Monsanto, Cargill-Dow, Sygen International, Tyco Healthcare and others.
The BRDC has recently taken an equity stake in ZuChem, while many key firms are represented on the company's Scientific Advisory Board. Members include Dr David Ager (DSM Fine Chemicals), Dr Ian Fotheringham (Ingenza) and Dr David Dodds (former director of fermentation & biocatalysis development for Bristol-Myers Squibb). Added recently were Dr Robin Cooper of Rigel and Dr William Dowd, retired former global R&D director for industrial biotechnology with Dow Chemical.
ZuChem also supplies commercially valuable small molecules to other industries such as agriculture, flavours and fragrances and speciality chemicals. For the flavours and fragrances market, the company plans to introduce sugars and sugar derivatives that are already commercially available but at a significantly reduced cost. "We will continue to develop early stage novel, proprietary biocatalytic and other synthetic chemistry methods into economically viable manufacturing processes," says Friesema.
The technology ZuChem uses is based on a combination of enzymes and microorganisms. The company focuses on engineering enzymes and understanding the pathways used by microorganisms in order to modify them and achieve the desired reactivity under appropriate conditions. These efforts have resulted in technological developments that enable ZuChem to advance its process development activities forward in a more efficient manner, according to Friesema.
The company also combines its bioprocess expertise with synthetic chemistry to develop modified sugars.
In addition to its microbial production technologies for products such as mannitol and other related speciality polyol chemicals, ZuChem is also investigating microbial strains for bioprocess production of inositol derivatives. "We also intend to develop technologies to produce derivatives and combinatorial libraries of these compounds as second-generation products," Friesema says.
In pharmaceuticals, simple glycochemicals are used as fillers and formulation aids in tablet and capsule production because they are chemically inert and will not react with the active drug and because they also contribute sweetness with minimal calorie content. ZuChem is working to develop a number of technologies that could be used for the production of rare sugars and sugar derivatives that are not currently available.
These products are attractive because they have a number of established chiral centres. However, it is difficult to control the numerous stereochemical centres in sugar molecules with current technology. As a result, many isomers are typically produced that are very difficult, and usually very costly, to separate from the desired product. Many new drugs could be made if rare sugars and sugar derivatives could be obtained both in high yield and purity via a cost-effective process.
Glycochemicals are key components in many pharmaceutically active compounds, ranging from antibiotics to anti-cancer and anti-viral compounds (for example, AZT). Glyochemical-based drugs will have an estimated E15.6 billion market value in 2005 and the market for glycochemicals in fine chemicals is experiencing 10-20% growth every year, according to ZuChem.
Several glycochemical anti-virals, anti-cancer agents and drugs for metabolic disorders are currently in clinical trials. According to the company, the glycochemical aspect of a drug can generate €4-40 million/year per drug application. The potential is therefore significant.
It has been known for some time that the substitution on the sugar components of many macrolide antibiotics, such as vancomycin, is important for their binding and action. Additional investigations have also shown that less common unnatural carbohydrates may be important in antigen binding and recognition. Research is now expanding into the use of carbohydrate-containing glycoproteins and polysaccharides to modify, alter or disrupt such interactions in order to gain a therapeutic effect.
"The introduction of new sugars opens up the possibility of different binding mechanisms," says Friesema. "With the cost-effective production of rare sugars available to us, we may be able to design new drug candidates that can be targeted to specific binding sites. The result would be more effective drugs that require less active ingredient and have minimal side effects."
ZuChem will further derivatise its products with functional groups at certain sites within the sugar molecules
to make them even more attractive as pharmaceutical building blocks or intermediates. A number of different drug classes are expected to benefit from the introduction of these glycochemical intermediates, including insulin sensitisers for the treatment of type II diabetes, anti-virals, anti-microbials and anti-cancer agents.
In August, ZuChem began offering custom synthesis of rare and modified glycochemicals using its proprietary bioprocess technology. Selected product types include rare L-sugar derivatives, modified monosaccharides and other unusual glycochemicals. Specific services include small molecule glycosylation, microbial fermentation, biotransformations, biocatalyst engineering, process optimisation and scale-up and product recovery.
"We are extending our technologies to produce rare sugars and their derivatives for use as reagents or active building blocks for pharmaceuticals, and are using our technology in partnership with other companies that want to sponsor research into the development of specific products," says Friesema.
ZuChem has also raised more than €1.3 million in its Series A financing round, and is seeking additional capital and strategic partners for its Series B round. The company will be in-licensing some technologies that will enable it to meets its long-term goals, and expects to start a new round of financing late in 2004 or in early 2005. "We are seeking partners to commercialise the bioprocesses under development for the various markets ZuChem has targeted," says Friesema. "The market potential for glycochemicals in these industry sectors is significant. We have demonstrated that our technology is viable and ZuChem fully intends to capitalise on these opportunities in the near future."