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.
Organisations
Publications
A Celik
(2007)
Direct Biocatalytic Conversion of Carbon Dioxide: Towards a Formic Acid Economy
in in preparation
A Celik
(2007)
Creating new Tools for a Formic Acid Economy: Cloning & Structure of Novel Dehydrogenases
in in preparation
Aljabali A. A. A.
(2014)
Multimeric microparticles of iron oxide (mMPIO) for dual modality molecular imaging with CT & MRI
in EUROPEAN HEART JOURNAL
Allman SA
(2009)
Potent fluoro-oligosaccharide probes of adhesion in Toxoplasmosis.
in Chembiochem : a European journal of chemical biology
Baboo S
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Most human proteins made in both nucleus and cytoplasm turn over within minutes.
in PloS one
Backus KM
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The three Mycobacterium tuberculosis antigen 85 isoforms have unique substrates and activities determined by non-active site regions.
in The Journal of biological chemistry
Backus KM
(2011)
Uptake of unnatural trehalose analogs as a reporter for Mycobacterium tuberculosis.
in Nature chemical biology
Bagi Zsolt
(2013)
Microparticles bearing RGD peptide promote integrin avß3-dependent platelet adhesion in isolated, pressurized cerebral artery
in FASEB JOURNAL
Barry C
(2013)
'Naked' and Hydrated Conformers of the Conserved Core Pentasaccharide of N-linked Glycoproteins and Its Building Blocks
in Journal of the American Chemical Society
Barry CS
(2011)
ESI-MS assay of M. tuberculosis cell wall antigen 85 enzymes permits substrate profiling and design of a mechanism-based inhibitor.
in Journal of the American Chemical Society
Bernardes G
(2007)
A trisulfide-linked glycoprotein
in Chemical Communications
Bernardes GJ
(2008)
Facile conversion of cysteine and alkyl cysteines to dehydroalanine on protein surfaces: versatile and switchable access to functionalized proteins.
in Journal of the American Chemical Society
Bernardes GJ
(2008)
From disulfide- to thioether-linked glycoproteins.
in Angewandte Chemie (International ed. in English)
Bernardes GJ
(2011)
Site-selective traceless Staudinger ligation for glycoprotein synthesis reveals scope and limitations.
in Chembiochem : a European journal of chemical biology
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
Bernardes Goncalo J. L.
(2012)
Building well-defined glycoproteins
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
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
Boutureira O
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Direct radiolabelling of proteins at cysteine using [18F]-fluorosugars.
in Chemical communications (Cambridge, England)
Boutureira O
(2009)
Accessible sugars as asymmetric olefin epoxidation organocatalysts: glucosaminide ketones in the synthesis of terminal epoxides.
in Organic & biomolecular chemistry
Boutureira O
(2012)
Selenenylsulfide-linked homogeneous glycopeptides and glycoproteins: synthesis of human "hepatic Se metabolite A".
in Angewandte Chemie (International ed. in English)
Boutureira O
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in Chemical communications (Cambridge, England)
Boutureira Omar
(2012)
Chemical site-selective radiolabelling of proteins using fluorosugars
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
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(2007)
Chemical and chemoenzymatic synthesis of glycosyl-amino acids and glycopeptides related to Trypanosoma cruzi mucins.
in Organic & biomolecular chemistry
Chalker J
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Methods for converting cysteine to dehydroalanine on peptides and proteins
in Chemical Science
Chalker JM
(2009)
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in Chemistry, an Asian journal
Chalker JM
(2010)
Chemical mutagenesis: selective post-expression interconversion of protein amino acid residues.
in Current opinion in chemical biology
Chalker JM
(2011)
A "tag-and-modify" approach to site-selective protein modification.
in Accounts of chemical research
Chalker JM
(2012)
Conversion of cysteine into dehydroalanine enables access to synthetic histones bearing diverse post-translational modifications.
in Angewandte Chemie (International ed. in English)
Chalker JM
(2009)
A convenient catalyst for aqueous and protein Suzuki-Miyaura cross-coupling.
in Journal of the American Chemical Society
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Enabling olefin metathesis on proteins: chemical methods for installation of S-allyl cysteine.
in Chemical communications (Cambridge, England)
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(2011)
Suzuki-Miyaura cross-coupling on protein substrates using a novel palladium-pyrimidine catalyst
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Chalker Justin M.
(2011)
Reaction engineering for protein modification
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Chalker Justin M.
(2011)
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in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
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in JOURNAL OF PEPTIDE SCIENCE
Chooi K. Phin
(2014)
Giving p38a kinase a jump-start: p38a Activation induced by chemical modification
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Chooi KP
(2014)
Synthetic phosphorylation of p38a recapitulates protein kinase activity.
in Journal of the American Chemical Society
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(2012)
Phosphine-free Suzuki-Miyaura cross-coupling in aqueous media enables access to 2-C-aryl-glycosides.
in Organic letters
Cocinero EJ
(2011)
Sensing the anomeric effect in a solvent-free environment.
in Nature
Cocinero EJ
(2009)
The building blocks of cellulose: the intrinsic conformational structures of cellobiose, its epimer, lactose, and their singly hydrated complexes.
in Journal of the American Chemical Society
Cocinero EJ
(2013)
Free fructose is conformationally locked.
in Journal of the American Chemical Society
Cocinero EJ
(2009)
Peptide secondary structures in the gas phase: consensus motif of N-linked glycoproteins.
in Journal of the American Chemical Society
Cocinero EJ
(2009)
Hydration of sugars in the gas phase: regioselectivity and conformational choice in N-acetyl glucosamine and glucose.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Cocinero EJ
(2008)
Conformational choice and selectivity in singly and multiply hydrated monosaccharides in the gas phase.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Cocinero EJ
(2011)
Exploring carbohydrate-peptide interactions in the gas phase: structure and selectivity in complexes of pyranosides with N-acetylphenylalanine methylamide.
in Journal of the American Chemical Society
Cruz IN
(2013)
Glycomimetic affinity-enrichment proteomics identifies partners for a clinically-utilized iminosugar.
in Chemical science
Davis B
(2009)
A silver-lined anniversary of Fleet iminosugars: 1984-2009, from DIM to DRAM to LABNAc
in Tetrahedron: Asymmetry
Davis B
(2009)
Sugars and proteins: New strategies in synthetic biology
in Pure and Applied Chemistry
Davis Ben
(2012)
Sugars and proteins
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Davis Ben
(2007)
Sugar solutions - Interview
in MOLECULAR BIOSYSTEMS
| 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/ |