Chemical Biology
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Group Expertise
The Chemical Biology group brings together scientific expertise in a broad range of areas, from medicinal chemistry to cell biology:
I. Medicinal chemistry
The group takes a variety of approaches to access new areas of chemical space – from the rational design of small molecular probes and inhibitors for therapeutically interesting targets (e.g., glycosyltransferases, immunoglobulin G) to novel approaches in natural product chemistry. Synthetically, the group has particular strengths in peptide, nucleotide, carbohydrate and heterocyclic chemistry, and in the chemical modification of nanoparticles for targeted drug delivery. The group also has a strong interest in marine natural products, to explore the potential of natural products derived from marine symbiosis for drug discovery.
Natural product chemistry is also represented by the development of novel analytical approaches to the standardisation of complex mixtures as in plant extracts, and also the use of informatics in drug discovery.
II. Bioinorganic chemistry
The group has a world-leading reputation for its contributions to the development of clinically-useful iron chelators. Deferiprone, the first orally active iron chelator introduced into man was designed by Professor Bob Hider\'s research group. The drug is already used worldwide for the treatment of iron overload, and the group is now exploring its potential for the treatment of various forms of neurodegeneration as well as parasitic infections.
III. Bioanalytical chemistry
The Chemical Biology group is the home of one of the few international laboratories capable of the synthesis and quantitation of hepcidin, a master regulator of iron metabolism. The hepcidin assay developed in Dr Sukhi Bansal\'s laboratory is currently being used in clinical studies carried out with Novartis and Vifor Pharma. The group also has expertise in the use of mass spectrometry for metabolomics.
IV. Cell biology
The group has established models in several prokaryotic and eukaryotic organisms, including yeast and C. elegans, for applications in Chemical Biology. The group of Dr Colin Dolphin, for example, has developed novel methodologies enabling high-throughput, and large-scale recombineering for high fidelity gene expression analysis in C. elegans.
1. The function of the molecular chaperone Hsp90
Heat shock protein 90 (Hsp90) is an ATP dependant molecular chaperone essential for both creating and maintaining the active conformation of key regulatory proteins, such as certain hormone receptors, mitogen activated protein kinases and tumour suppressors such as p53 and Rb. In order to achieve its function, Hsp90 acts as the centre of a multi-protein chaperosome complex that includes an array of co-chaperones. The chaperosome complex has been highly conserved throughout the eukaryotic lineage, and we exploit yeast as a genetically tractable model system in which to investigate the contribution made by each co-chaperone to the overall function of the chaperosome. For example, we can assess activity of Hsp90 substrates - such as the glucocorticoid receptor and the pp60v-src oncogernic kinase - in genetic backgrounds deleted for the genes encoding the co-chaperones.
2. The role played by the Smc5/6 complex in maintenance of genome integrity
There are three Structural Maintenance of Chromosomes complexes. The core of all three is composed of a heterodimer. One complex, cohesin (Smc1/3), keeps sister chromatids together prior to mitosis. Condensin (Smc2/4), is responsible for the chromosome condensation that occurs during mitosis. The third, Smc5/6, has an essential yet poorly characterised role. We are trying to understand the role played by this complex in maintaining genome integrity. Smc5/6 is found in a complex containing at least five other proteins, Nse1-5 (Non Smc Elements). We are generating mutant alleles of the corresponding genes, in order to observe how they disturb genome structure, thereby generating insight into the function of the Smc5/6 complex itself.
3. Conditional mutants in QRI2/NSE4 arrest at the G2/M transition
Cells deleted for NSE4 bearing a vector-borne wild type allele (W+), or the nse4-4ts allele, were grown at 250C and shifted to 370C for 4 hours. Cells were fixed, followed by staining DNA and spindles with DAPI (B), and anti-tubulin (C), respectively. Panels A (phase), B & C are cells from the same field of view.
BV vectors as potential gene delivery vehicles
BV is an insect virus that has been exploited over many years to direct expression of foreign proteins in insect cell cultures. Because the range of post-translational modifications, e.g. glycosylation, mediated by insects are, in comparison to bacteria or yeast, more similar to those of mammalian cells the baculovirus expression vector system (BEVS) has gained considerable popularity. BV can also transduce and deliver a functional gene to the nuclei of a range of mammalian cells often with efficiencies >90%. The list of non-host cells transduced successfully has grown in recent years and includes several examples of human primary cells, e.g., hepatocytes, neural cells and pancreatic islet cells. BV exhibits several features that make it attractive as a vehicle for in vitro gene delivery to mammalian cells and as a potential alternative to more traditional viral vectors for in vivo gene therapy. The Chemical Biology group are modifying the genome of BV with the aim of developing it as a therapeutically viable gene therapy vector. In particular the interest is in targeting baculovirus to specific cell populations in the liver that regulate the extra-cellular matrix remodeling that is critical in the pathogenesis of cirrhosis. The lack of any effective small molecule anti-fibrotic drug class represents a critical and pressing unmet clinical need for this disease and we hope to develop alternative therapeutic strategies based on BV gene therapy.
Recombineering reporter fusions
In collaboration with the Hope lab (http://bgypc059.leeds.ac.uk/~web/), we have developed a strategy, based on recombineering with a counter-selection cassette, to directly, and seamlessly, modify genomic fosmid clones to generate fusion reporters for analyzing gene expression in C. elegans. The method was described in Dolphin CT, Hope IA. (2006). Further information, including a FAQs page, on the group recombineering protocol can be found here.
Gene targeting in C. elegans
Since its adoption as a genetically tractable model animal the nematode C. elegans has provided invaluable, detailed insight into numerous fundamental biochemical processes. Many of these discoveries were and are still made using classical forward "phenotype-to-gene" genetic screens. However, in contrast to several other models, such as mouse and yeast, it has not yet proved possible in C. elegans to generate precise sequence changes at genomic loci via homologous recombination (HR). Thus, a robust and facile gene-targeting (GT) method remains a highly desirable and sought-after functional genomics tool for worm researchers. The group is hoping to develop a new approach for GT in C. elegans based upon HR mediated by bacteriophage recombinases.
- Metabonomics “The quantitative measurement of the multivariate metabolic responses of multicellular systems to pathophysiological stimuli or genetic modification”. (GLOBAL SYSTEM ANALYSIS) Nicholson et al, Xenobiotica 1999. In particular for application in toxicity, disease and nutrition.
- Fundamentals of liquid chromatography and applied liquid chromatography coupled to mass spectrometry (in particular micro and nano LC for high sensitive analysis of small molecules and peptides)
- Capillary Electrochromatography/Electrophoresis and applications.
- Ultra Performance liquid chromatography and applications.
- NMR analysis (1D, 2D and MAS) of biofluids and tissues.
- Advanced statistical analysis (chemometrics)
- Chromatographic methods to calculate phase-analyte interactions (frontal analysis approach)
- Molecularly imprinted polymers. MIPs
- Validation of analytical methods
Dr Mountford's research interests are primarily focussed on the interface between biology and chemistry, particularly the way in which chemistry can be used to modulate biological processes, specifically the effect of small molecules in oncology and inflammation.
During an inflammatory response there is extravasation of leukocytes from the blood to tissues, in cancer metastasis there is an analogous extravasation of tumour cells from the blood. Selectins, integrins and chemokines are intimately involved in the rolling, activation, adhesion and transmigration of leukocytes; antagonism of specific targets in this cascade has been shown to lead to a reduction in the recruitment of tumour cells from the blood.
A complementary approach is to target the mechanisms involved in tumour growth. Angiogenesis, the growth of new blood vessels from pre-existing vessels occurs when a tumour attains a critical mass to ensure that adequate oxygen and nutrients are supplied while toxic metabolites are removed. An anti angiogenic therapy would render a tumour dormant, limiting metastasis via migration of cells from the tumour and in addition would improve the effectiveness of existing cancer therapies.
To facilitate the investigation of these processes new methods and approaches will be required both in terms of chemical synthesis and Medicinal Chemistry.
Dr Wagner's main research interests are in medicinal chemistry and chemical biology – developing chemical tools to address biological and biomedical problems. Research in his laboratory sits at the interface of chemistry and biology and research projects in his group - such as the development of inhibitors and assays for therapeutically relevant enzymes - are generally very interdisciplinary. Dr Wagner and his group use a range of different methods, from organic synthesis, through protein biochemistry to various analytical techniques, particularly fluorimetry. The Wagner group collaborates extensively with external partners in the UK, Denmark and Germany.
Current projects:
Glycosyltrasferases as drug targets
Glycosyltransferases (GTs) are enzymes that catalyse the transfer of a monosaccharide from a glycosyl donor to a suitable acceptor, e.g. a glycan, peptide or lipid (see e.g. Annu. Rev. Biochem. 2008, 77, 521-555). GTs play a key role in many biological processes underpinning human health and disease, including glycoprotein and cell wall biosynthesis in human pathogens, carcinogenesis, and cellular adhesion. Individual GTs represent promising therapeutic targets, and the Wagner group is developing small molecular GT inhibitors as lead compounds for drug discovery, and as chemical tools for the investigation of glycosylation networks in living systems (Nat. Chem. Biol. 2010, 6, 321-323.)
Synthetic modifications of biomolecules in aqueous solution
Dr Wagner and his group have developed synthetic methodology for the direct structural modification of sensitive biomolecules in aqueous media, obviating the need for protecting groups and for lengthy synthetic sequences. The group has particular expertise in the Pd-catalysed cross-coupling of nucleosides, nucleotides, sugar-nucleotides and amino acids. This synthetic approach has proved very useful for the generation of novel fluorescent bioprobes.
Chemical tools for NAD-dependent enzymes
The dinucleotide NAD (nicotinamide adenine dinucleotide) is required as a cofactor not only by redox enzymes, but also by other enzyme classes which use NAD for covalent modifications. Many of these enzymes, such as the PARP enzymes, the sirtuins, and NAD-dependent ligases, play essential roles in cell signalling and transcription, and are exciting molecular targets for chemical biology and drug discovery. Dr Wagner and his group are currently developing structural analogues of NAD for the selective inhibition of individual enzymes and for the real-time imaging of their activity, e.g. in living cells.
Dr Thanou and her group prepare fluorescent nanoparticles and study their diffusion in biological samples using Multiple particle Tracking and fluorescent microscopy
Engineering targeted nanoparticles for cancer siRNA delivery
Dr Thanou and her group have developed a novel ligand for breast and prostate cancer that can functionally deliver siRNA to tumours. They studied and optimised the organisation of this ligand on the surface of Nanoparticles for optimum receptor recognition and endocytosis.
Developing Carbon Nanopipes as drug delivery systems
Dr Thanou and her group are developing novel carbon architectures that can be used safely for biomedical applications. These architectures show chemical versatility and the potential to be used in Drug Delivery.
Using experimental and bioinformatics approaches, Dr Long’s research focuses on how biosynthetic pathways have evolved to generate the rich chemical diversity found within living cells. By studying biosynthesis at the molecular level in Streptomyces bacteria and during complex marine invertebrate-microbial symbioses, Dr Long hopes to gain insight into the chemical ecology of these compounds and to assess their potential for drug discovery.
- Structure-function studies of the p53 family of transcription factors and their role in cancer and other human diseases
- Protein stability, protein (mis)folding, aggregation and disease
- Protein-protein, protein-DNA interactions.
Professor Peter Hylands has many years experience in natural product research and development, with an emphasis on the isolation and structural determination of novel bioactive compounds, both in academia and industry.
Professor Hylands has led multidisciplinary research programmes in Europe, the Americas and various Asian countries and has been an invited speaker all over the world. Important aspects of his present research are innovative chemometric metabonomic approaches to natural product research, notably the standardisation of plant extracts.
Alzheimer's disease – the production of amyloid-ß by the sequential actions of ß- and ß-secretase, and its subsequent aggregation into senile plaques, is one of the hallmarks of Alzheimer’s disease (AD).
Dr Parsons' research has investigated how protein lipidation (palmitoylation and isoprenylation) regulates the protein:protein interactions between ß-secretase (BACE1) and other proteins involved in its subcellular trafficking. BACE1 undergoes highly-regulated subcellular trafficking within the cell, and within certain subcellular regions BACE1 associates with its substrate, APP, leading to cleavage and production of amyloid-ß.
Dr Parsons' research has shown that inhibition of these protein lipidation reactions results in altered subcellular trafficking and reduced amyloid-ß. In collaboration with colleagues from St. George's, University of London, he is currently investigating the role that protein isoprenylation has in the amyloid-ß-induced inflammatory response.
Parkinson's disease - dysfunctional energy metabolism is present in many neurodegenerative diseases, which arises from reduced Complex I activity. The highly oxidising environment within the dopaminergic neurones of the substantia nigra, the neurones which degenerate in Parkinson's, leaves them particularly susceptible to reduced Complex I activity.
Dr Parsons is interested into how N-methylation biotransformation of proneurotoxins is involved in the pathogenic process. His research has shown that the enzyme nicotinamide N-methyltransferase (NNMT), which converts nicotinamide (a form of vitamin B3) into 1-methylnicotinamide, is significantly higher in PD brain than in disease-control brain. This appears to be a neuroprotective response of the cell to the underlying pathogenic process, as 1-methylnicotinamde is neuroprotective towards dopaminergic neurones, increasing Complex I activity and stabilising its structure.
Also, overexpressing NNMT in a dopaminergic neuronal cell-line leads to increased cell viability and Complex I activity. In collaboration with colleagues both within the Division and at Imperial, the next stage in Dr Parsons' research is to design lead compounds which exploit this neuroprotective action of 1-methylnicotinamide, which may provide a viable therapeutic avenue for the treatment of PD.
Other research interests:
- Combinatorial chemistry
- Anti-sense therapeutics
- Biomimetic catalysis
