A review of the emerging field of artificial biology mediated by Pd chemistry in ChemBioChem has highlighted development of this field by the Davis group. Palladium-mediated carbon-carbon bond formation plays a revolutionary role in advancing organic synthesis and now has the potential to create a new 'Pallado-Biology'.
A recent paper from the BGD group describing a new biocatalytic method for attaching pure glycans to intact antibodies (and has the potential to allow the development of finely-tuned mAb-based drugs) has been spotlighted in JACS.
Ben Davis has been given the RSC 2012 Bioorganic Award for "his work on carbohydrates and their protein partners revealing fundamental mechanisms behind their structures and bond-forming processes and exploiting this understanding in synthesis and technology.".
The BBSRC, the UK biological research council, has highlighted work from the group.
Justin Chalker and Lukas Lercher's recent work on synthetic histone proteins has been featured as a Hot Paper in Angewandte Chemie. In a collaboration with Nathan Rose from the CJS group, they created synthetic chromosome-associated proteins (histones) that are able to act as proper mimics with so called writer/eraser and reader proteins for the first time.
Research from the group has been featured on the cover of Chemical Science. The image depicts the key findings in the associated publication in which multiple methods for the conversion of cysteine to dehydroalanine and its use in covalent protein modification are described. The cover artwork was designed by Yuya A. Lin of the Ben Davis group.
Ben Davis has been awarded the Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry for 2012.
Justin Chalker was a finalist in the 2012 Reaxys PhD Prize for which he will receive a bursary to travel to the 14th Asian Chemical Congress, on September 7th 2011 in Bangkok.
Smita Gunnoo won a poster prize at the 2011 UCB-Celltech UK Science Day.
Recent work that comes from a collaboration between the Barry group at the US NIH and the Davis group has described the first small molecule that can be used to detect TB. The work, published in Nature Chemical Biology has been featured in Chemistry World, in Nature's Research Highlights, and by the University of Oxford's Science Blog.
Sander van Kasteren, who worked in the group for his DPhil, has just won a Biochemical Society Early Career Research Award.
Our recent article in Nature was featured in a Nature commentary on the future of Chemistry in the 2011 International Year of Chemistry, on the University website, and in Chemical and Engineering News.
Work by Omar Boutureira and co-workers from the BGD group on fluoro-glycoprotein synthesis has been highlighted in Chemical Communications as a HOT Article and also featured on a Cover and ChemComm blog. Researchers developed a tag-and-modify strategy that allows the practical synthesis of homogenous fluorinated glyco-amino acids, peptides and proteins carrying a fluorine label in the sugar, allowing access to the first set of examples of directly radiolabelled ([18F]-glyco)proteins
A paper that describes the total and reveals the mechanism of pectin self-assembly bulds on the Oxford rich tradition of jam technology and has been featured on the front cover of the June 2 issue of J. Am. Chem. Soc.
Ben Davis was selected as a finalist for the BBSRC Innovator of the Year 2010.
Two Davis group papers were amongst the most accessed for the year of 2009 in their respective journals: Justin Chalker, GonÌ¤alo Bernardes and Angel Lin's Cys-modification review in Chem Asian J., and Angel Lin and Justin Chalker's review on Olefin Metathesis in ChemBioChem.
Ben Davis has been selected for the Society of Synthetic Organic Chemistry, Japan (SSOCJ) Lectureship Award for 2010 and will give this lecture in September 2010. The last and only other UK recipient was Steve Davies in 1998.
Elsevier has selected a group image to be the feature cover for Carbohydrate Research in 2010. The cover illustrates research by the group and was designed by Karl Harrison.
Justin Chalker and Charlotte Wood (Part II in 2008/9) have had their paper on Pd-mediated protein reactions highlighted by F1000, by Chemical & Engineering News (Nov 2009), and by ChemCatChem. The research-recently reported in the Journal of the American Chemical Society-features a novel water-soluble catalyst for Suzuki-Miyaura cross coupling. The catalyst enabled the first Suzuki-Miyaura cross-coupling on protein substrates and is also useful in small molecule synthesis.
Filip Wyszynski won one a 2009 Final Year Graduate Symposia prize awarded by AstraZeneca for his talk on the work that he has been conducting during his DPhil.
Work by the group on the development of a putative HIV vaccine has been highlighted the Times
Ben Davis appeared and was troubled by some worryingly basic questions in the new series of the Channel 5 'What in the World' quiz show screened during the autumn of 2009.
Work of the group in Synthetic Biology has been highlighted in an article written in Chemistry World.
Work by Justin Chalker, Angel Lin and Omar Boutureira from the group on protein cross metathesis that appears in Chem. Commun. as a hot article has been highlighted by the RSC's popular science news magazine Chemical Science.
Keriann Backus, a 2nd year student from the group and part of the joint NIH-Oxford programme, was awarded the 'Pfizer Outstanding Poster Prize' at the Bioorganic Gordon Conference held at the Proctor Academy, June 14-19, 2009. Samantha Shanley, a 4th year student from the group was also awarded the Jeremy R. Knowles Memorial Travel Scholarship to attend the same GRC.
Work by Paul Gardner (conducted in collaboration with Klaus Winzer from Nottingham) has been highlighted in a News & Views article. Paul's work itself appears in the August issue of Nature Chemistry and reports how they have constructed a lipid-bound protometabolism that synthesizes complex carbohydrates from simple feedstocks, which are capable of engaging the natural quorum sensing mechanism of the marine bacterium Vibrio harveyi and stimulating a proportional bioluminescent response.
The Norman Heatley Award has been given to Professor Davis for his outstanding and innovative contributions to protein-carbohydrate chemical biology. The award is new and is given to early career researchers to recognise and promote the importance of inter- and multi-disciplinary research between chemistry and the life sciences.
Prof Gouverneur likes steak & chips, Prof Davis likes bread. Veronique Gouverneur (4 May 2009 issue) and Ben Davis (18 May 2009 issue) have both been selected by Angewandte Chemie for author profiles, which recognise the publication of more than ten papers in the journal since 2000.
The Novartis Institutes for Biomedical Research have selected Ben Davis for a 2009-2010 Novartis Chemistry Lectureship Award. This lecture award, to be given as a series at the Novartis sites around the world, focuses on synthetic organic chemistry and cutting edge chemistry.
Work by the Davis group, conducted in collaboration with the Sibson (ROB) and Anthony (Pharmacology) groups, describing new glyconanonparticles that are capable of imaging brain diseases such as MS, has been highlighted by PNAS and Chemical & Engineering News. The paper describing this work appears in the January 6 issue of the Proceedings of the National Academy of Sciences.
Keri Backus and Mitul Patel were awarded a Commendation for their work on transfer from PRS to DPhil status.
A recent publication from the Ben Davis group was highlighted in Chemical & Engineering News and in Nature Chemical Biology. The work was led by Yuya Angel Lin, a Part II student from Keble College. The authors have discovered that allyl sulfides are efficient substrates in aqueous cross-metathesis. The enhanced reactivity derives from a unique sulfur relay of the alkene to the ruthenium catalyst. The high reactivity of allyl sulfides in cross-metathesis was exploited in the first examples of cross-metathesis on a protein surface, setting a new standard in substrate sensitivity and complexity in olefin metathesis and expanding the toolkit for protein modification.
Ben Davis has been awarded by the ACS Carbohydrate Division the 2008 Horace S. Isbell Award for outstanding contributions to the field of carbohydrate chemistry. The award recognizes carbohydrate scientists under the age of 41 who have demonstrated excellence in the field and show promise of continuing to make high-quality contributions to carbohydrate chemistry and biochemistry. It is the first time someone in the UK has won this honour.
The group's recent publication in J. Am. Chem. Soc., detailing an alternative route to prepare Dehydroalanine (Dha) - an important chemical handle for selectively modifying proteins - has been highlighted in Chemical & Engineering News and in Nature Chemical Biology.
Samantha Shanley has won the Graduate Presentation prize at the RSC Carbohydrate Group Spring 2008 Meeting held in Oxford on 07-08 April 2008.
Paul Gardner, a 3rd year student in the Davis group won first prize for his poster "Quorum Sensing of Formose: Towards Artifical Cell - Natural Cell Communication" at the European Science Foundation meeting on Synthetic Biology.
A paper by Sander van Kasteren and Holger Kramer, from the Davis group, on the "Synthesis of Glycoproteins" appeared on the front cover of the December issue of Nature Protocols.
Justin Chalker has won one of the 2007 Eli Lilly Year Student Awards for Organic Chemistry based on his PRS Transfer Report and Viva.
A panoramic library: Multiwell library screening of acceptor structures has allowed the identification of the first examples of glycosynthase enzymes that utilize non-natural substrates. In their Communication in Angewandte Chemie, G. Davies, B. Davis, and M. Yang show that the novel specificity, activity, and catalytic efficiency of the mutants are comparable with those of natural glycosyltransferases. The cover shows a 360å¡ view of the multiwell ceiling of Oxford's Radcliffe Science Library.
Recent work from the groups of Prof. John Simons and Prof. Ben Davis on probing aromatic-sugar complexes has been selected as a frontispiece for Angewandte Chemie. Sugar-arene complexes have been created in molecular-beam experiments and observed by IR ion-dip spectroscopy in the gas phase. These complexes are powerful models of the selective recognition seen in protein-sugar complexes, for example between the galactose-specific lectin from Artocarpus hirsute and MeGal.
The paper in Nature by Sander I. van Kasteren, Holger B. Kramer, Henrik H. Jensen, Sandra J. Campbell, Joanna Kirkpatrick, Neil J. Oldham, Daniel C. Anthony and Benjamin G. Davis which provides a new way of detecting biological structures could help in the fight against disease. The new method, developed by scientists at Oxford University, uses chemistry to assemble proteins into 'protein probes' that can be sent into the body to, for instance, detect inflammation and disease in the brain. > more
Ben Davis has been awarded one of the Royal Society of Chemistry's 2005 Corday-Morgan Medals for contributions to synthetic carbohydrate chemistry and glycobiology. He has also been awarded the 2006 International Association for Protein Structure Analysis and Proteomics Young Investigator Award.åÊ
Ben Davis is the recipient of the 2005 Royal Society Mullard Award "for hisåÊpioneering work onåÊcarbohydrate and enzyme/proteins and for recognising the commercial potential of his research."
Hagan Bayley, Ben Davis, Neil Oldham and Chris Schofield have been awarded a 5-year grant of å£1.6 million by the BBSRC under the initiative "Selective chemical intervention in biological systems". The funds are for the discovery of small molecules that can be used to explore the roles of the post-translational modification of proteins in living cells. The team aim to create an international resource in this area.
Ben Davis and Prof. Anne Dell (Imperial College) discussed the role of carbohydrates on the BBC Radio 4 The Material World programme (2 June 2005).
ACS and Chemical & Engineering News have chosen a paper from Ben Davis' group on Glycodendriproteins as one of the Chemical Highlights of 2004.
An approach to drug delivery using novel carbohydrates to carry drugs has recently been described in the Proceedings of the National Academy of Sciences. The method exploits the abundance of lectins, or carbohydrate-binding receptors, on the surface of specific cells. The authors demonstrate the delivery of the cancer drug doxorubin targeted to hepatocytes in a mouse liver tumour model.
Known as the LEAPT strategy, lectin-directed enzyme-activated prodrug therapy is a two-stage delivery system. First, a novel non-mammalian glycosidase enzyme, rhamnosidase, is conjugated to a mammalian sugar; this is taken into the target cell by sugar-mediated receptor-mediated endocytosis, via the asialoglycoprotein receptor, a membrane-bound endocytic lectin found in abundance on the surface of hepatocytes in the liver. The second step involves administering the rhamnose-capped pro-drug; the drug is activated in the target cell once the sugar cap is removed by the pre-delivered rhamnosidase enzyme. The rhamnosidase enzyme was isolated from Penicillium decumbens and its carbohydrate structure was specifically engineered through enzymatic de-glycosylation and chemical re-glycosylation with mammalian sugar residues such as mannose and galactose.
Both in vitro and in vivo techniques proved the delivery of rhamnosidase and prodrug to hepatocytes and demonstrated successful activation of the rhamnose-bound prodrug. The authors tested the therapeutic effectiveness of LEAPT by constructing a doxorubicin prodrug, Rha-DOX, and using it in a hepatocellular carcinoma disease mouse model. After 42 days of therapy, the liver tumour burden was shown to have decreased by almost half compared with the control groups receiving either Rha-DOX or glycosylated rhamnosidase alone.
LEAPT achieves higher concentrations of active drug at the target site through the use of engineered glycosylated enzymes than delivery of drug alone. Assuming that suitable receptors can be identified, delivery to other cell types is possible simply by changing the cognate sugar attached to the enzyme. The use of macrophage-associated carbohydrate receptors to treat macrophage-associated diseases such as lysosomal storage diseases or viral infections could benefit from this approach.
Researchers develop protein copies which make bacteria impotent.
Concerns in hospitals about bacterial resistance to current antibiotic treatments continue to rise and global research teams are racing to develop new antibiotics to outwit the pathogens. Now an international team of researchers has approached the problem from a new angle, finding a way to make bacteria impotent by preventing them from binding to cell surfaces.
Many pathogens, including bacteria, bind to host cell surfaces through branched, complex carbohydrate structures on glycoproteins. In a bid to disarm bacteria, the researchers, led by Ben Davis at the University of Oxford, UK, decided to construct copies of these structures. They focused on glycodendrimers, which mimic the branched carbohydrates on glycoproteins. To make copies of glycoproteins, Davis and coworkers then attached glycodendrimers to a protein to form a new class of compounds which they labelled glycodendriproteins.
Bacteria stick to cell surfaces using adhesins, which often form from sugar-binding proteins called lectins. The team claims that its glycodendriproteins attach to lectin adhesins on bacteria and selectively degrade them. This leaves the bug without a method of binding to the host and so leaves it handless explains Davis. Very early observations suggest that the treatment doesnt seem to kill the pathogens but makes them impotent, he says.
According to Davis, a number of pathogens, including viruses, use the same mode of binding: grappling host carbohydrates before infection. By interfering with the modes of binding, Davis hopes to be able to retool the system to almost any target that uses this strategy, simply by changing the sugars and the level of valency of the glycodendrimer. He thinks that the glycodendriprotein method may be used to construct mimics of almost any naturally occurring glycoproteins. There is a wealth of potential applications for such structures in chemical glycobiology and related therapeutic areas. We are pretty excited about what these punters could do, exclaims Davis. And it seems that other researchers in the field are keen on the work too, with Anne Dell, professor of carbohydrate chemistry at Imperial College London, considering it to offer exciting possibilities.
Genencor, a US biotechnology company, provided some funding for the work. Davis says that the firm hopes to develop drugs based on the glycodendriproteins. Until now, the project has been driven from the academic side, he says.
As bacteria become resistant to existing antibiotics, scientists around the world are searching for new approaches. The latest comes from an international group of chemists from the UK, US and Canada. They propose to use branched sugar-like molecules, called glycodendrimers, to grasp germs in a sticky embrace. Attached to the glycodendrimer is an enzyme that will destroy bacterial proteins.
In laboratory tests the group, led by Ben Davis of Oxford University, showed that the approach worked against a germ called Actinomyces naeslundii. By changing the shape of the glycodendrimer, the chemists hope to make it bind to different bacteria. Their study is published in the Journal of the American Chemical Society.
"We are trying to block infection before it even gets going," says Mr Davis. "The glycodendrimer inhibits the binding but then the enzyme that is attached to the glycodendrimer swings around, chews up the protein on the surface and renders it unable to grab hold of the host it wants to infect." Oxford University: www.ox.ac.uk
Enzymes equipped with grappling hooks can disable pathogenic bacteria, according to Phillip M. Rendle and colleagues. They have found a way to tether a protease (protein-degrading enzyme) to the cell walls of Actinomyces naeslundii bacteria so that the enzyme can break down proteins that the bacteria use to invade their host.
Actinomyces naeslundii stick to human oral cavities and surgical prostheses through adhesin proteins in the bacterial cell walls, which bind to sugar (galactose) molecules. Rendle et al. figured that galactose groups attached to proteases would enable the enzymes to latch on to A. naeslundii , which would not only suppress the bacterium's stickiness by plugging their adhesin sites but would also wreak havoc when the enzyme got to work on the bacterial cell-wall proteins.
A single galactose tether is not enough, however. So Rendle et al. fixed branched tethers (dendrons) at selected positions on the proteases. Dendrons with two, three or four sugar tips give the enzyme a secure hold, with two tips being optimal for this bacterium. In preliminary tests, these modified proteases appear to inhibit A. naeslundii at concentrations of just 20 nanomolar.
A novel type of conjugate of carbohydrates and protein--known as a "glycodendriprotein"--may provide a new route to antibiotics.
Chemist Benjamin G. Davis of the University of Oxford, in England; microbiologist Marjorie M. (Kelly) Cowan of Miami University of Ohio, Oxford; and coworkers have shown that by linking branched carbohydrate-tipped structures known as glycodendrimers to a protein-degrading enzyme, they can inhibit the infectivity of the bacterium Actinomyces naeslundii [J. Am. Chem. Soc., 126, 4750 (2004) ].
Davis and his colleagues are targeting bacteria earlier in the infection process than most antibiotics do. "We're trying to block infection before it even gets going," he says. "The glycodendrimer inhibits the binding, but then the enzyme that is attached to the glycodendrimer swings around, chews up the protein on the surface, and renders it unable to grab hold of the host it wants to infect."
The glycodendrimers consist of sugar molecules on the tips of an antenna-like scaffold formed by such dendrimeric core molecules as TREN [tris(2-aminoethyl)amine] or mesitylene. Testing glycodendrimers with different numbers of antennae, the researchers found that a pair of antennae, with a total of two sugar residues, was the optimal number for the antibacterial system. For an alternative carbohydrate-binding protein, they found that a pair of branched antennae displaying four sugars was best.
The glycodendrimers are attached to the protease subtilisin through a cysteine linkage. Because subtilisin contains no naturally occurring cysteines, the positions where cysteines are inserted determine the locations of the carbohydrate on the protein. The carbohydrate targets and binds to receptors on the surface of A. naeslundii . Then the subtilisin chews up the protein adhesin on the bacterial cell surface. The carbohydrates successfully direct an otherwise nonspecific protease to the target protein. "We deliberately chose an enzyme that was very broad so that all we had to do was retool the enzyme with the appropriate targeting ligand," Davis says.
Davis believes the approach of synthesizing glycoproteins is flexible enough to be applied to a variety of systems. "There are a vast array of carbohydrate-binding proteins out there," he says. "You can basically pick the carbohydrate you need and then retool the end of the dendrimer for that function."
Carolyn R. Bertozzi, professor of chemistry at the University of California, Berkeley, who also studies glycoconjugates, calls this work an interesting approach to blocking bacterial adhesion and targeting receptors for degradation. "While bacterial proteins can become resistant to drugs via rapid mutation, the actual carbohydrate-binding residues in these bacterial adhesins are under pressure to remain conserved, as they are vital for the colonizing activity of the bacterial cell," Bertozzi says. "Thus, any approach that targets the carbohydrate-binding activity is less likely to suffer from the selection of resistant strains. Although its reduction to clinical practice is a ways off, as a concept, I think this is an interesting combination of antiadhesive therapy and receptor-mediated drug delivery that will prompt new ways of thinking about antibiotic design."
Last updated: 04-04-13
Prof Ben G. Davis
University of Oxford
Chemistry Research Laboratory
Oxford, OX1 3TA, UK
Phone: + 44 (0)1865 275652
Fax: + 44 (0)1865 275674