Professor Helen C. Hailes
Helen Hailes is a Professor of Chemical Biology and has a strong record of interdisciplinary research and collaborations with industry. She has extensive expertise in sustainable synthesis for the preparation of chiral synthons using biocatalysts in single-step reactions, multi-step cascades and reactions in water. In addition, she investigates the synthesis of tools to identify, image or perturb biological targets and synthesise compounds with improved biological properties, particularly anti-bacterials. She also has experience in the design and synthesis of novel lipids and lipid-conjugates for multifunctional nanoparticle assembly to be used in therapeutic delivery and imaging. She currently leads a multidisciplinary research group of 5 PhD students and 4 post-doctoral researchers, together with several Masters students.
She joined UCL in 1994 as a Lecturer, and in 2002 became a Senior Lecturer. In 2006 she became a Reader of Chemical Biology and in 2010 a Professor of Chemical Biology. Prior to joining UCL she carried out post-doctoral research at the University of Cambridge and Imperial College London.
|Summary of research group|
Current research themes include:
Research activity in our group is focused on the use of sustainable strategies for the preparation of chiral synthons using biocatalysts in single-step reactions, multi-step cascades as sequential steps or synthetic biology pathways, and also reactions in water. The use of biocatalysts for the synthesis of chiral compounds and fine chemicals is of significant interest to the chemical, pharmaceutical and industrial biotechnology sectors in the search for sustainable, cost effective, synthetic strategies.
The BiCE (Biocatalysis integrated with Chemistry and Engineering) http://www.ucl.ac.uk/biochemeng/industry/bice research programme with an internationally recognised multidisciplinary research team was established in 2004 with the overall aim to develop a framework and tools for constructing multi-step enzymatic processes rapidly and efficiently, ultimately for industrial synthesis. BiCE collaborators include Prof. G. J. Lye, Prof. J. M. Ward and Prof. P. A. Dalby. The enzymes transketolase (TK) and transaminase (TAm) were initially used as BiCE model systems, and when used sequentially as an early synthetic biology example they generated 2-amino-1,3-diols. Using an integrated strategy we established new chemistries and assays, identified novel biocatalysts and used directed evolution strategies, together with automated microscale experimentation and process modelling, to achieve rapid and predictive process scale-up.
We are currently investigating applications with TKs, TAms and other biocatalytic enzymes including cytochrome P450s, Baeyer-Villiger monooxygenases, norcoclaurine synthases, decarboxylases, halohydrin dehalogenases and alcohol dehydrogenases. In addition we are using metagenomics strategies for new enzyme discovery, and sugar-beet pulp bio-derived feedstocks in biocatalytic and chemical transformations. Several highlights of current work are detailed below.
Transketolases: For example using wild-type E. coli TK, libraries of active site mutants have been generated that were screened using a colorimetric assay. S- and R- selective TKs were identified, and strategies for the generation of stable double/triple mutants were established. We are currently investigating mutants that can accept a wide range of aliphatic aldehydes as well as aromatic substrates in high yields, and aldehydes accepted are shown in the scheme below.
Transaminases (TAms): New w-transaminases were obtained by BLAST searching with the reported V. fluvialis w-TAm sequence. Iteration of approach has generated >150 new TAms. The TAms have been screened to biotransform TK products with different amine donors and two-step TK+TAm reactions have been achieved in a dual plasmid E.coli strain, which provided an example of an early synthetic biology pathway. Several TAm assays have also been developed. We are currently using TAms in a wide range of applications including the generation of aminated steroids, kinetic resolutions, multi-step enzyme pathways, and chemo-enzymatic cascades.
Norcoclaurine Synthases (NCSs): In plant biosynthesis the first committed step to the benzylisoquinoline alkaloids, a large group of bioactive plant secondary metabolites, is catalysed by NCS. We are currently investigating NCSs including their characterisation, substrate tolerance, and biocatalytic applications. We have recently established a phosphate-mediated biomimetic NCS Pictet-Spengler reaction and several native recombinant NCSs were generated: CjNCS and TfNCS were used in substrate screening studies and preparative reactions to novel tetrahydroisoquinoline alkaloids achieved in >95% ee. The results provided mechanistic insights and a new ‘dopamine first’ mechanism was postulated and investigated which has been crucial for the rational engineering of NCS activity. High-throughput assays have been developed and ~40 NCS variants generated following the mechanistic studies. Some variants showed different (and improved) activity profiles against several aldehydes. We are currently investigating the use of these NCSs in enzymatic cascades and chemo-enzymatic cascades to novel single isomer alkaloids.
Novel lipid synthesis and nanoparticles for delivery and imaging applications.
We have been investigating the design and synthesis of novel lipids and lipid-conjugates for multifunctional nanoparticle assembly to be used in therapeutic delivery and imaging. This work is being carried out with collaborators including Prof. A. B. Tabor (Chemistry), Prof. M. J. Lawrence (Institute of Pharmaceutical Science, King’s College London) , Prof T. Ng (Randall Division, King’s College, London).
A particular focus has been the preparation of shielding lipids, possessing short n-ethylene glycol moieties, for use in targeted ternary lipid/peptide/DNA (LPD) nanocomplexes that are stable in the systemic circulation but dismantle once internalised. In recent work LPD gene delivery vectors, incorporating novel C14 glycerol based lipids of varying alkyl chain geometry, and multifunctional receptor-targeted nanocomplexes for magnetic resonance imaging and transfection of neuroblastoma tumours have been developed. As part of a Comprehensive Cancer Imaging Centre (CCIC) programme we have also developed a “toolbox” of lipid components that can be used to formulate self-assembling multifunctional nanoparticles for the simultaneous delivery of therapeutic entities and multimodal imaging. We are currently investigating applications with the lipid conjugates.
In current studies we are synthesising a series of novel isoquinolines with anti-tuberculosis properties, and investigating the mode of action in collaboration with Dr Sanjeeb Bhakta (Birbeck, University of London)
"Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines" B. R. Lichman, J. Zhao, H. C. Hailes, J. M. Ward, Nature Commun., 2017, 8, 14883; 10.1038/NCOMMS14883. Read me
Reaction cascades have recently been developed for the one-pot enzymatic synthesis of benzylisoquinoline alkaloids and chemoenzymatic synthesis of a tetrahydroprotoberberine [B. R. Lichman, E. D. Lamming, T. Pesnot, H. C. Hailes, J. M. Ward, “One-pot triangular chemoenzymatic cascades for the syntheses of chiral alkaloids from dopamine”, Green Chemistry, 2015, 17, 852–855]
A new colorimetric assay has been developed to screen transaminases using an inexpensive amine donor. The method is sensitive, has a low level of background coloration, and can be used to identify and profile transaminase activities against aldehyde and ketone substrates in a high-throughput format. It is also amendable to solid phase colony screening.
|Research facilities we use include MS, NMR, HPLC, GC.|
|Member, Royal Society of Chemistry|
• Sustainable synthetic strategies and reactions in water
• Stereoselective synthesis using biocatalysts
• Enzymatic and chemoenzymatic multi-step reaction cascades
• Novel lipid synthesis and nanoparticles for delivery and imaging applications
• Tuberculosis chemotherapies
|1st year workshops and laboratory demonstrating; 2nd year undergraduate lectures (spectroscopy); 2nd year organic tutorials and laboratory demonstrating; 4th year biosynthesis and biotransformation|