Creating a Synthetic Platform for Understanding and Exploiting Glycoconjugates

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry

Abstract

The evidence for the importance of carbohydrates in biology is increasing exponentially. Unlike other biomolecules (lipids, proteins, nucleosides) significant expertise is needed in the construction of corresponding glycoconjugate probes used to understand and exploit this biology: for example, no automated oligosaccharide synthesizer to date exists for the construction of all the glycoside linkages. The possible permutations for something as simple as the hexasaccharide structures stretch to greater than 1.05 x 1012 possible combinations. This level of complexity highlights that synthesis of glycoconjugates must be guided by functional design, and cannot simply be achieved through random synthesis of all possible combinations. There are a number of startling and challenging high-risk problems that exist in the field of glycoscience that the Platform would allow us to tackle. The risk is high, the challenges of complexity great (due, in part, to the typical lack of direct genetic control of glycoconjugate synthesis within biology) but the potential rewards are tremendous.

Publications

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Allman SA (2009) Potent fluoro-oligosaccharide probes of adhesion in Toxoplasmosis. in Chembiochem : a European journal of chemical biology

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Bernardes G (2007) A trisulfide-linked glycoprotein in Chemical Communications

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Bernardes GJ (2011) Site-selective traceless Staudinger ligation for glycoprotein synthesis reveals scope and limitations. in Chembiochem : a European journal of chemical biology

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Bernardes GJ (2008) From disulfide- to thioether-linked glycoproteins. in Angewandte Chemie (International ed. in English)

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Bernardes Goncalo J. L. (2012) Building well-defined glycoproteins in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY

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Bernardes Goncalo J. L. (2012) Chemical site-selective protein modification: Development of a traceless vascular targeting ADC for cancer therapy in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY

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Bolam DN (2007) The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity. in Proceedings of the National Academy of Sciences of the United States of America

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Boutureira O (2010) Fluoroglycoproteins: ready chemical site-selective incorporation of fluorosugars into proteins. in Chemical communications (Cambridge, England)

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Boutureira O (2011) Direct radiolabelling of proteins at cysteine using [18F]-fluorosugars. in Chemical communications (Cambridge, England)

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Boutureira Omar (2012) Chemical site-selective radiolabelling of proteins using fluorosugars in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY

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Chalker JM (2009) Enabling olefin metathesis on proteins: chemical methods for installation of S-allyl cysteine. in Chemical communications (Cambridge, England)

 
Description This Platform grant allowed us scientific freedom to explore some highly unconventional ideas for how molecules containing sugars (so-called glycoconjugates) might work in nature and might be used in medicine. From this work we have discovered new sugar-based drugs to treat disease (including new classes of antibiotics), new ways of detecting disease at a much earlier stage (e.g. TB or MS) and new ways of understanding how nature handles and builds sugars.
Exploitation Route The fundamental discoveries are allowing those interested in applications, such as diagnosing or treating disease to do this based on a better understanding. We too are developing these techniques, in partnership with leading clinicians.
Sectors Agriculture, Food and Drink,Chemicals,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://users.ox.ac.uk/~dplb0149/
 
Description BGD and group members have appeared on the radio, television, (BBD, Channel 5), newspapers and journals (The Times, The Herald, New Scientist) science festivals around the world (Cheltenham, Kent, Edinburgh, Times Lit., Sydney) describing this work. We have given talks in schools to inspire the next generation. The work contributed strongly to industrial growth in the biotech sector worldwide and was cited in the BBSRC Innovator of the Year Finalist Citation 2010 for BGD, for example. BGD talked about this work at the Parliamentary and Scientific Committee.
First Year Of Impact 2007
Sector Chemicals,Creative Economy,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal,Economic,Policy & public services

 
Description BBSRC Grouped
Amount £508,027 (GBP)
Funding ID BB/J009725/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 12/2014
 
Description BBSRC Grouped
Amount £508,027 (GBP)
Funding ID BB/J009725/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 12/2014
 
Company Name Glycoform Ltd 
Description drug delivery and glycoprotein specialist; biopharmaceuticals 
Impact Employed >20 people over 10 years and provided a model for how synthetic protein drugs might be constructed and used. The technology for this company has now been used by major US companies.
Website http://isis-innovation.com/news/glycoform-ltd-improve-drug-delivery/