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Details of Grant 

EPSRC Reference: EP/C006372/1
Title: HighThroughput Screening in Biochemical Synthesis: Development of Biocatalysis Chips
Principal Investigator: Millner, Professor P
Other Investigators:
Researcher Co-Investigators:
Professor P Hodge
Project Partners:
Department: Inst of Molecular & Cellular Biology
Organisation: University of Leeds
Scheme: Standard Research (Pre-FEC)
Starts: 14 February 2005 Ends: 13 June 2005 Value (£): 19,500
EPSRC Research Topic Classifications:
Combinatorial Chemistry Materials Synthesis & Growth
EPSRC Industrial Sector Classifications:
Manufacturing Chemicals
Food and Drink Pharmaceuticals and Biotechnology
Related Grants:
Panel History:  
Summary on Grant Application Form
High throughput screening systems (HTS) in chemical screening are in the main directed at the pharmaceutical industries to identify and test compounds that have the possibility of becoming useful drugs of the future. The whole high throughput area has been generated by the need to screen huge libraries of potential compounds for biomolecular interactions with their targets, including 'gene chips' and 'protein chips' where multi-arrays of DNA or protein sequences are immobilised and presented in parallel to samples to identify targets from a large number of possible candidates. HTS has not been directly applied to biocatalysis as far as is known, and the production of 'biocatalyst chips' is a concept that would assist in the rapid development of new biochemical synthetic routes for chemical substances useful in many areas of industry, including pharmaceutical intermediates. 'biocatalyst chip' may be defined as a device having a number of different biocatalytic areas that may or may not be interconnected, and which may be contacted by potential chemical candidates dissolved in a solvent system in a parallel fashion. Such devices may or may not be used as simultaneous analytical systems or synthetic systems depending on their construction. As with existing chip technology, biocatalyst immobilisation will be necessary to allow parallel synthesis and in biocatalysis the actual presentation of the substrates to the biocatalyst is often crucial for reaction to take place / e.g. dispersions of powdered lipases in solvents may give a catalytic profile, but the same lipases adsorbed onto polymer beads and presented to the same substrate may give a different catalysis profiles and rates.With this in mind two main routes will be followed: 1) The production of chips having a single type of patterned immobilisation matrix, that will allow simultaneous deposition of multiple biocatalytic enzymes. This will allow screening of immobilisation properties of the enzymes on the matrix used and also the identification of which enzyme on which support gives the correct reaction. 2) The production of chips having multiple patterned immobilisation matrices to allow the deposition of a single enzyme for biocatalytic screening. This will allow a multiple number of parameters to be determined simultaneously for the biocatalytic enzyme being screened, e.g. activity, efficiency, stability, chemistry occurring, biocatalytic capability and solvent resistance. With data from both chip types, hybrid systems with different immobilisation matrices and multiple enzymes will be able to be constructed for selected reaction types for HTS of chemical synthetic routes, i.e. customised 'biocatalysis chips' for particular reaction types. The practical route to producing biocatalyst chips requires a series of clear steps and the formation of a very multidisciplinary team working both individually yet fitting into the whole project for success. Step 1. The design of the chip structure. Parallel address systems and micro-fluidic reagent supply. Step 2. Production of immobilisation matrices. Polymer science to give surfaces, porosity, chemistry and micro-environments to allow efficient attachment of the biocatalytic enzymes. Step 3.Actual manufacture of chips. Matrix density to fit in with fluidics. Step 4. Immobilisation chemistry. Functionalisation of polymer matrices, production and use of tagged biocatalytic enzymes, development of ubiquitous methods for all enzymes / screening for efficiency of immobilisation and activity retention. Step 5.Detection techniques for products of biocatalytic reactions. Off chip or on chip will be explored. Step 6. Additional techniques to improve biocatalytic capabilities. Use of electrochemistry, local heating, acoustic stimulation, pulse techniques. Step 7. Testing of chips with selected reaction chemistries for demonstration of utility. Biocatalysis enzymes for project demonstration will be lipases and cytochrome p450s.
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Organisation Website: http://www.leeds.ac.uk