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Professor Helen Hailes

Recent News

BiCE Team UCL wins RSC Rita & John Cornforth Award

BiCE Team UCL, with Prof Helen Hailes in Chemistry as the Team Leader, has been awarded the 2010 Rita and John Cornforth Award of the Royal Society of Chemistry (RSC) for for the use of key chemical biology and synthetic skills, interfaced with molecular biology and process engineering to achieve stereoselective enzymatic synthesis with potential for industrial scale-up. More information can be found here.

Research Overview

Research activity in our group is focused on the use of synthetic organic chemistry to probe and solve biological problems. Many of our projects involve the development of new synthetic strategies to construct molecules as tools to identify or perturb biological targets, which can lead to the identification of novel compounds with improved biological properties. We are also interested in the use of water as a reaction solvent and the use of catalytic, biocatalytic and chemoenzymatic synthetic strategies.

Chemoenzymatic and Biocatalytic Synthesis of Aminodiols (BiCE Project)

Helen Hailes OBC journal cover image

This major EPSRC interdisciplinary research project set out to establish a systematic approach to achieving the integration of chemical, biocatalytic and bioprocess strategies for the synthesis of key chiral synthons. The project is in collaboration with Prof. G. J. Lye(Biochemical Engineering), Dr. J. M. Ward (Biochemistry), Dr. P. A. Dalby (Biochemical Engineering), Dr. F. Baganz (Biochemical Engineering), Dr M. Micheletti (Biochemical Engineering) Dr N. Szita (Biochemical Engineering) and Prof. J. M. Woodley(Chemical Engineering, DTU, Denmark). The synthesis of novel aminodiols is being investigated through the linkage of advanced biotransformations: C-C bond formation using transketolase (TK), reductive amination using transaminase (TAm), and molecular evolution techniques are being developed to enhance the component enzymes.

The biocatalytic formation of acyclic α,α'-dihydroxyketones by TK is well documented in the literature, but in this project we have discovered a novel atom efficient one-pot synthesis of dihydroxyketones in water via a mimic of the transketolase reaction. The formation of a quaternary ammonium enolate is postulated in this tertiary-amine mediated carbon-carbon bond forming reaction. In order to identify TK mutants and active TAms the development of assays and chiral assays is crucial: we have recently identified a colorimetric assay for TK high throughput applications and the use of LC-MS is has been developed for high-throughput aminodiol screens. Chiral assays have also been developed for the α,α'-dihydroxy ketone products and using this new mutants generated that are able to generate either the (R)- or (S)- product in high e.e.s. Novel highly stereospecific ω-transaminases have also been identified that can convert α,α'-dihydroxyketones to aminodiols. Further studies include the use of TK and TAm in target molecule synthesis.

Example of using colorimetric assay to identify new active TK mutants

We have also started to explore the use of alternative enzymes to benzylisoquinoline alkaloids. Our approach is to bring together synthetic biology, chemistry and pathway engineering to create bacteria that synthesise chemically diverse compounds of this class. 

The synthesis of PI 3-kinase and PKB activators and inhibitors

The project aims to identify novel PI 3-kinase and PKB activators and inhibitors to facilitate research into the role and interactions of PI kinases and is in collaboration with Dr.R.Woscholski (Department of Biological Sciences, Imperial College). Research into PI 3-kinases has benefited enormously from the availability of specific inhibitors; however, having only inhibitors greatly restricts the investigations that can be performed. Recently, compound 48/80, an oligomeric mixture of methylene linked aryl compounds, was identified as having activating properties towards PI 3-kinase. From this initial lead compound we have developed solid phase methodologies to synthesise a range of analogues and identified a novel, selective PKB inhibitor.

Non-Viral Gene Therapy

A major collaborative research initiative has been established to investigate the structural requirements for lipids in a highly efficient ternary synthetic gene transfection system comprised of a lipid (L comprised of a cytofectin such as DOTMA and helper lipid DOPE)), targeting peptide (I) and DNA (D). This work is being carried out in collaboration with Dr.A.B.Tabor (Chemistry), Dr S. L.Hart (Institute of Child Health, UCL) and Professor M.J.Lawrence (Department of Pharmacy, KCL). These ternary lipopolyplex LID systems display high transfection efficiency and low toxicity in vitro and in vivo, transfect non-dividing cells efficiently, and are well tolerated with low immunogenicity in vivo. In this project we are tackling the major issues relating to vector efficacy including targeting, and the influence of the structure of the lipid on particle stability. We have established that shorter unsaturated lipid chains lead to enhanced transfection in several cell-types, most likely due to better membrane disruption or enhanced targeting, and that in the LD system the optical purity of the cytofectin may be important. We have also designed and synthesised two series of novel lipids, which enhance transfection efficacy due to better particle stability. In addition, we have studied the structure and fate of the aggregate formed using confocal microscopy and FCS (collaboration with Dr D. Zicha, ICRF) via the synthesis of specifically labelled lipids. Particle size, zeta potential and particle stability studies have been carried out. For in vivo applications, as well as incorporating PEG linkers to aid particle stability we have also introduced cleavable moieties to enhance release from the endosome.

Chemical structures of DOTMA, DOPE and Peptide I
Reaction scheme involving lipids, DOPE and peptide/DNA complex

In a recent work on a collaborative EPSRC Nanotechnology Grand Challenge grant we are investigating the use of nanoparticles for the targeted delivery of therapeutic agents to the brain for the treatment of dementias. The aim is to deliver DNA, siRNA and therapeutic drugs to the brain using our targeted ternary delivery vectors comprised of designer lipids and peptides. Also, as part of the multidisciplinary King's College London and UCL Cancer Imaging Centre with Prof. T. Ng and 27 other scientists, we are developing new strategies for in vivo cancer imaging. The main clinical objective of the EPSRC/CRUK funded CCIC is to develop and provide a comprehensive range of imaging technologies which, when combined with molecular and genetic information, will begin to accurately characterize individual patients for the ultimate goal of personalized therapy.

Calixarenes and Tuberculosis Therapies

We are investigating the synthesis and biological activity of a series of calixarenes and novel small molecule analogues with anti-TB activities. To date, we have established efficient synthetic methodologies to prepare a range of novel calix[8]arenes with PEG moieties attached at the lower rim via ether linkages. Testing in vivoestablished preliminary structure–activity relationships, with some compounds exhibiting significant anti-mycobacterial activity. The calixarenes appear to act via a novel host macrophage mediated mechanism, involving the up-regulation of arginase and functioning iNOS . Further studies are underway using labelled calixarenes to probe this novel mechanism of action through a collaboration with Prof. D. Young (NIMR, Mill Hill).

Chemical structure of Calix[8]arenes


Design and Synthesis of Novel Hydrogen Bonding Arrays

This research project has focused on the synthesis of novel ureidopyrimidinones, incorporating functionalities to enhance hydrogen-bonding in the dimerization motifs generated. New hydrogen-bonding cytosine-based motifs have also been designed and synthesised and the dimerisation constants studied using NMR techniques with Dr. A. E. Aliev (Chemistry). This module, which can readily be difunctionalised, has been used in the synthesis of a range of novel polymers with interesting properties, and further module structural design is underway.

Model showing hydrogen bonding array

The Synthesis of Novel Signaling Molecules

Projects have focused on identification of the methodology and design and synthesis of molecules for use in electrochemically based medical diagnostic assays incorporating ferrocene. Multifunctional ferrocenyl-fatty acid conjugates were designed and synthesised to establish the key properties required for use in biomolecular binding studies between fatty acids and human serum albumin. This powerful modular design strategy can be applied to other electrochemical probe systems in order to investigate biomolecular interactions.

Organic Synthesis in Water

For several years we have been interested in performing carbon-carbon bond forming reactions in aqueous media. We reported the first Diels-Alder reaction in homochiral aqueous micellar media where enantioselectivities were observed. More recently we have reported the first acid catalysed aqueous Baylis-Hillman reaction and a novel mimetic of the enzymatic transketolase reaction in water.

Selected Publications and Patents:

  1. G. Herve, D. Uwe Hahn, H. C. Hailes, A-C. Herve, K. J. Goodworth, and A. M. Hill, " The Selective Functionalisation and Difunctionalisation of p -Substituted Calix[6]arene and Calix[8]arenes using Hydrophilic Moieties", Org. Biomol. Chem., 2003 , 1 , 427-435.
  2. C. A. Hurley, H. C. Hailes, A. B. Tabor and S. L. Hart. Complexes for the delivery of biologically-active material to cells. PCT Int. Appl. (2003), 66 pp. WO 2003/094974
  3. M. J. Colston, H. C. Hailes, E. Stavropoulos, A. C. Hervé, G. Hervé, K. J. Goodworth, A. M. Hill, P. Jenner, P. D. Hart, and R. E. Tascon, "Antimycobacterial Calixarenes Enhance Innate Defence Mechanisms in Murine Macrophages and Induce Control ofMycobacterium tuberculosis Infection in Mice", Infect. Immun. 2004 , 72, 6318-6323 .
  4. M. J. Writer, B Marshall, M. A. Pilkington-Miksa, S. E. Barker, M. Jacobsen, P. C. Bell, D. H. Lester, A. B. Tabor, H. C. Hailes , N. Klein, and S. L. Hart, "Targeted Gene Delivery to Human Airway Epithelial Cells with Synthetic Vectors Incorporating Novel Targeting Peptides Selected by Phage Display", J. Drug Targeting , 2004 , 12 (4), 185-194.
  5. C. A. Hurley, J. B. Wong, H. C. Hailes, and A. B. Tabor, "Asymmetric Synthesis of Dialkyloxy-3-Alkylammonium Cationic Lipids" J. Org. Chem. 2004 , 69 , 980-983.
  6. P. A. Dalby, H. C. Hailes, J. Ward, J. M. Woodley, E. Hibbert, F. Baganz, and G. Lye, "Directed evolution of biocatalytic processes",Biomolecular Engineering, 2005 , 22, 11-19 .
  7. P. Caumul and H. C. Hailes, “Baylis-Hillman Reactions in Aqueous Acidic Media“, Tetrahedron Lett.2005, 46, 8125–8127.
  8. V. G. H. Lafitte, A. Aliev, H. C. Hailes, K. Bala, and P. Golding, “Ureidopyrimidinones Incorporating a Functionalisable p-Aminophenyl Electron-Donating Group at C-6”, J. Org. Chem. 2005, 70, 2701–2707.
  9. K. Bala and H. C. Hailes, “Nitrile Oxide 1,3-Dipolar Cycloadditions in Water: Novel Isoxazoline and Cyclophane Synthesis”,Synthesis2005, 3423–3427.
  10. Erika Rosivatz, H. C. Hailes, M. Numbere, and R.Wosholski, "Novel compounds, which are useful as inhibitors and/or activators of protein kinase B (PKB/Akt)", UK patent application, March 9 2005, P37370GB.
  11. V. G. H. Lafitte, A. E. Aliev, P. N. Horton, M. B. Hursthouse, and H. C. Hailes, “Highly Stable Cyclic Dimers Based on Noncovalent Interactions”, Chem. Commun.2006, 2173–2175.
  12. V. G. H. Lafitte, A. E. Aliev, P. N. Horton, M. B. Hursthouse, K. Bala, Peter Golding, and H. C. Hailes, “Quadruply Hydrogen Bonded Cytosine Modules for Supramolecular Applications”, J. Am. Chem. Soc.2006, 128, 6544–6545.
  13. M. E. B. Smith, K. Smithies, T. Senussi, P. A. Dalby, and H. C. Hailes, “The First Mimetic of the Transketolase Reaction”, Eur. J. Org. Chem. 2006,1121–1123.
  14. M. E. B. Smith, U. Kaulmann, J. M. Ward, and H. C. Hailes, “A Colorimetric Assay for Screening Transketolase Activity”, Bioorg. Med. Chem.2006, 14, 7062–7065.
  15. I. Tranchant, A.-C. Hervé, S. Carlisle, P. Lowe, C. J. Slevin, C. Forssten, J. Dilleen, R. Bhalla, D. E. Williams, A. B. Tabor, and H. C. Hailes, “Design and Synthesis of Ferrocene Probe Molecules for Detection by Electrochemical Methods”, Bioconjugate Chem.2006,17, 1256–1264.
  16. M. Writer, C. A. Hurley, S. Sarkar, D. M. Copeman, J. B. Wong, M. Odlyha, M. J. Lawrence, A. B. Tabor, R. J. McAnulty, P. A. Shamlou, H. C. Hailes and S. L. Hart, “Systematic analysis and Optimisation of the Cationic Lipid Component of Lipoplex and Lipopolyplex Formulations for Efficient Gene Transfer”, J. Liposome Res. 2006, 16, 373–389.
  17. I. Tranchant, A.-C. Hervé, S. Carlisle, P. Lowe, C. J. Slevin, C. Forssten, J. Dilleen, A. B. Tabor, D. E. Williams and H. C. Hailes, “Applications of Tailored Ferrocenyl Molecules as Electrochemical Probes of Biochemical Interactions”, Bioconjugate Chemistry,2007, 18, 199–208.
  18. H. C. Hailes, Reaction Solvent Selection: The Potential of Water as a Solvent for Organic Transformations, Org. Process Res. Dev.2007, 11, 114–120.
  19. U. Kaulmann, K. Smithies, M. E. B. Smith, H. C. Hailes, and J. M. Ward, Substrate spectrum of w -transaminase fromChromobacterium violaceum DSM30191 and its potential for biocatalysis, Enz. Microb. Tech . 2007 , 41, 628–637.
  20. H. C. Hailes, P. A. Dalby and J. M. Woodley, “Integration of biocatalytic conversions into chemical syntheses”, J. Chem. Tech. Biotech. 2007, 82, 1063–1066.
  21. U. Kaulmann, K. Smithies, M. E. B. Smith, H. C. Hailes, and J. M. Ward, Substrate spectrum of w -transaminase fromChromobacterium violaceum DSM30191 and its potential for biocatalysis, Enz. Microb. Tech. 2007, 41, 628–637.
  22. C. U.Ingram, M. Bommer, M. E. B. Smith , P. A. Dalby, J. M. Ward, H. C. Hailes, and G. J. Lye, “ One-pot Synthesis of Amino-Alcohols Using an engineered a De-novo Transketolase and b-Alanine:Pyruvate Transaminase Pathway in Escherichia coli Escherichia coli”, Biotech. Bioeng.2007, 96, 559–569.
  23. E. G. Hibbert, T. Senussi, S. J. Costelloe, W. Lei, M. E. B. Smith, J. M. Ward, H. C. Hailes, P. A. Dalby, “ Directed evolution of transketolase activity on non-phosphorylated substrates”, J. Biotechnology 2007, 131, 425–432.
  24. M. F. M. Mustapa, P. C. Bell, C. A. Hurley, A. Nicol, E. Guénin, S. Sarkar, M. J. Writer, S. E. Barker, J. B. Wong, M. A. Pilkington-Miksa, B. Papahadjopoulos-Sternberg, P. Ayazi Shamlou, H. C. Hailes, S. L. Hart, D. Zicha and A. B. Tabor, "Biophysical Characterisation of an Integrin-Targeted Lipopolyplex Gene Delivery Vector", Biochemistry, 2007, 46, 12930-12944.
  25. M. A. Pilkington-Miksa, M. J. Writer, S. Sarkar, Q.-H. Meng, S. E. Barker, P. Ayazi Shamlou, H. C. Hailes, S. L. Hart, and A. B. Tabor, "Targeting Lipopolyplexes Using Bifunctional Peptides Incorporating Hydrophobic Spacer Amino Acids: Synthesis, Transfection and Biophysical Studies", Bioconjugate Chem. 2007, 18, 1800-1810.
  26. . A. Irvine, Q. H. Meng, F. Afzal, J. Ho, J. B. Wong, H. C. Hailes, A. B. Tabor, J. R. McEwan, S. L. Hart S. L, "Receptor Targeted Nanocomplexes Optimized for Gene Transfer to Primary Vascular Cells and Explant Cultures of Rabbit Aorta", Molecular Therapy,2008, 16, 508-515.
  27. E. G. Hibbert, T. Senussi, M. E. B. Smith, S. J. Costelloe, J. M. Ward, H. C. Hailes, P. A. Dalby, "Directed evolution of transketolase substrate specificity by targeted mutagenesis", J. Biotechnology, 2008, 134, 240-245.
  28. M. A. Pilkington-Miksa, S. Sarkar, M. J. Writer, S. E. Barker, P. Ayazi Shamlou, S. L. Hart, H. C. Hailes and A. B. Tabor, "Synthesis of Bifunctional Integrin-Binding Peptides Containing PEG Spacers of Defined Length for Non-Viral Gene Delivery", Eur. J. Org. Chem., 2008, 2900-2914.
  29. A. D. Tagalakis, R. J. McAnulty, J. Devaney, S. E. Bottoms, J. B. Wong, M. Elbs, M. J. Writer, H. C. Hailes, A. B. Tabor, C. O'Callaghan, A. Jaffe and S. L. Hart, "A receptor-targeted nanocomplex vector system optimized for respiratory gene transfer", Molecular Therapy, 2008, 16, 907-915.
  30. J. B. Wong, S. Grosse, A. B. Tabor, S. L. Hart, and H. C. Hailes, "Acid Cleavable PEG lipids for Applications in a Ternary Gene Delivery Vector", Mol. BioSyst., 2008, 4, 532-541.
  31. C. A. Hurley, J. B. Wong, J. Ho, M. Writer, S. A. Irvine, M. J. Lawrence, S. L. Hart, A. B. Tabor and H. C. Hailes, "Di- and Monocationic short PEG and Methylene Dioxyalkylglycerols for use in Synthetic Gene Delivery Systems", Org. Biomol. Chem.,2008, 6, 2554-2559.
  32. M. M. L. M. Vareiro, I. Tranchant, S. Maplin, K. Zak, M. M. Gani, C. J. Selvin, H. C. Hailes, A. B. Tabor, P. J. Cameron, A. T. A. Jenkins, D. E. Williams, "Surface plasmon resonance-enhanced fluorescence implementation of a single-step competition assay: Demonstration of fatty acid measurement using an anti-fatty acid monoclonal antibody and a Cy5-labeled fatty acid", Analytical Chem., 2008, 377, 243-250
  33. M. E. B. Smith, E. G. Hibbert, A. B. Jones, P. A. Dalby and H. C. Hailes, "Enhancing and Reversing the Stereoselectivity of Escherichia coli Transketolase via Single-Point Mutations", Adv. Syn. Cat., 2008, 350, 2631-2638.
  34. H. C. Hailes and R. G. Gunn, "Insights into the PI3K-PKB-mTOR Signalling Pathway from Small Molecule Probes", J. Chem. Biology,2008, 1, 49-62.
  35. M. F. M. Mustapa, S. M. Grosse, L. Kudsiova, M. Elbs, E. A. Raiber, J. B Wong, A. P. Brain, H. E. Armer, A. Warley, M. Keppler, T. Ng, M. J. Lawrence, S. L. Hart, H. C. Hailes, A. B. Tabor, “Stabilised Integrin-Targeting Ternary LPD (Lipopolyplex) Vectors for Gene Delivery Designed To Disassemble Within the Target Cell”, Bioconjugate Chem., 2009, 3, 518-532.
  36. K. K. Ho, E. Rosivatz, R. M. Gunn, M. E. B. Smith, A. V. Stavropoulou, E. Rosivatz, M. G. Numbere, J. B. Wong, V. G. H. Lafitte, J. M. Behrendt, S. S. Myatt, H. C. Hailes, R. Woscholski, E. W. F. Lam, “The novel molecule 2-(5-(2-chloroethyl)-2-acetoxy-benzyl)-4-(2-chloroethyl)-phenyl acetate inhibits PI3-K/Akt/mTOR signalling through JNK activation in cancer cells”, FEBS J., 2009, 276, 4037-4050.
  37. K. Smithies, M. E. B. Smith, U. Kaulmann, J. L. Galman, J. M. Ward, H. C. Hailes, “Stereoselectivity of an ω-transaminase-mediated amination of 1,3-dihydroxy-1-phenylpropane-2-one”, Tetrahedron: Asymm., 2009, 20, 570-574.
  38. J. L. Galman, H. C. Hailes, “Application of a modified Mosher's method for the determination of enantiomeric ratio and absolute configuration at C-3 of chiral 1,3-dihydroxy ketones”, Tetrahedron: Asymm., 2009, 20, 1828-1831
  39. H. C. Hailes, P. A. Dalby, G. J. Lye, J. M. Ward, “Biocatalytic approaches to ketodiols and aminodiols”, Chimica Oggi-Chemistry Today, 2009, 27, 28-31.
  40. M. E. B. Smith, B. H. Chen, E. G. Hibbert, U. Kaulmann, K. Smithies, J. L. Galman, F. Baganz, P. A. Dalby, H. C. Hailes, G. J. Lye, J. M. Ward, J. M. Woodley and M. Micheletti, "A Multidisciplinary Approach Toward the Rapid and Preparative-Scale Biocatalytic Synthesis of Chiral Amino Alcohols: A Concise Transketolase-/ω-Transaminase-Mediated Synthesis of (2S,3S)-2-Aminopentane-1,3-diol", Org. Process Res. Dev., 2010, 14, 99-107.
  41. A. Cázares, J. L. Galman, L. G. Crago, M. E. B. Smith, J. Strafford, L. Ríos-Solís,G. J. Lye, P. A. Dalby, H. C. Hailes, "Non-alpha-hydroxylated aldehydes with evolvedtransketolase enzymes", Org. Biomol. Chem., 2010, 8, 1301–1309.
  42. A. Chiva, D. E. Williams, A. B. Tabor, H. C. Hailes, "Screening of polymeric supports and enzymes for the development of an endo enzyme-cleavable linker", Tetrahedron Lett., 2010, 51, 2720-2723.

Links:

Editorial Board member for Journal of Chemical Biology

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 Editorial Board Member of New Journal of Chemistry