Oxford's first spin-off
Oxford GlycoSystems
In October 1988, with the help of Monsanto and Searle (which had just been acquired by Monsanto), the University of Oxford launched its first ever spin-off company in which the University had a shareholding. The idea was to develop further the sugar technology in order to make it available to users all over the world. Oxford
GlycoSystems was born as a technology company and succeeded in making several
different kinds of instruments to release sugars from proteins and then allow the full oligosaccharide sequence to be obtained. Within a few years, most of the major drug companies in the world had Oxford GlycoSystems’ instruments, as glycosylation became more important in the ‘quality control’ of glycoproteins. It was realized that in calthe production process, any slight variation, such as changing oxygen levels or cell culture conditions, could lead to a change in glycosylation pattern.
Biotechnology and glycosylation
In 1985, Raymond Dwek's group at Oxford University published a landmark patent on tissue plasminogen activator, a drug that dissolves clots after heart attacks and strokes5. This patent, which was largely based on the PhD work of Raj Parekh, taught that the actual glycoforms of a protein were important, rather than only the protein’s amino acid sequence. It was possible to distinguish different glycoforms, and therefore different products, from the same gene when expressed in two different cell lines. In terms of biotechnology, this put glycosylation very much to the forefront.
Glycosylation and hepatitis B and C: glycoprotein folding
In about 1990, Baruch Blumberg, who had received a Nobel Prize for his work on a vaccine for hepatitis B, joined the Glycobiology Institute, while he was Master at Balliol College, Oxford. Professor Tim Block, from Thomas Jefferson University, PA, came for a sabbatical with Blumberg and myself and we started an antiviral programme
in the Institute. Initially, we studied hepatitis B and demonstrated that the
secretion of the virus was inhibited in the presence of the drug NB-DNJ. At the same time in the Glycobiology Institute, work was underway by Stefana Petrescu (from the
Bucharest Institute of Biochemistry, Romania), using NB-DNJ to inhibit the
metalloglycoprotein tyrosinase, which is involved in melanin biosynthesis. This pointed to the involvement of calthe nexin in the ER (endoplasmic reticulum)
in glycoprotein folding, and this is still a pivotal result for glycobiology; it soon
became clear that many viruses also achieved the three-dimensional structure of their surface glycoproteins using the calnexin pathway. We showed that the action of NB-DNJ was as an inhibitor of glucosidase 1 and 2, and thus could prevent proper folding as it inhibited the interaction with calnexin.
Thus a large antiviral programme was begun, using imino sugars to create this misfolding. Today those studies have been expanded to hepatitis B and C,
under Nicole Zitzmann at the Glycobiology Institute, and she has a programme to develop a series of morphology inhibitors. Her article in this issue of The Biochemist (pp. 23–26) outlines an important aspect of the future programme. A clinical trial on hepatitis C has already been undertaken by United Therapeutics, USA, and more are planned.
Raymond Dwek, Glycobiology at Oxford, A personal view; www.bioch.ox.ac.uk
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