Drug Discovery
Figure 1 A fully-integrated fluidic
workflow allows the seamless joining of synthesis through to biological assay alongside
precise hardware control and integration of state of the art computational methods for compound design
described above contrasts with the equivalent process for the discovery of some biological thera- peutics, during which a candidate product may be identified in a timescale of a few months, before more rapidly progressing into development. The discovery process for monoclonal antibodies (mAb) has been continually transformed and improved by new technologies over the past two decades. It is now possible to create a mAb specif- ic to almost any extracellular or cell surface target and this technological revolution has driven a large amount of research and development with monoclonals for numerous serious diseases. Initially, murine antibodies were obtained by the now conventional hybridoma technology, which has proved very useful as a platform to generate pre-clinical research tools but allergic reactions in chronic use led to the overall clinical failure of most mouse antibodies, except in some specific circumstances. To reduce murine antibody immunogenicity, humanised antibodies are now produced by grafting murine amino acid domains into human antibodies, which results in a mAb of approximately 95% human sequence. As human- ised antibodies often bind antigen more weakly than the parent murine monoclonal antibody, increases in antibody-antigen binding strength have been achieved by various specialised tech- niques including the introduction of mutation. New human monoclonal antibodies are now dis- covered using transgenic mice or phage display libraries. Human monoclonal antibodies are pro- duced by transferring human immunoglobulin genes into the murine genome, after which the transgenic mouse is vaccinated against the desired antigen, leading to the production of monoclonal antibodies, allowing the transformation of murine
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antibodies in vitro into fully human antibodies. In essence, the mouse does most of the required molecular optimisation of the mAb required for the biological target, with some reprogramming by modern molecular biology techniques1. For a small-molecule drug discovery platform to approach the level of efficiency of the above-men- tioned mouse, a radically different approach to drug discovery needs to be adopted. The expedi- tious use of automation and emerging technologies now presents us with the opportunity to identify small molecules in a timeframe more usually asso- ciated with mAbs for the first time. This will lead to further downstream improvements to the over- all efficiency of the pharmaceutical industry, as small molecules drugs have lower cost of goods and are, generally, easier to develop than mAbs. A key requirement to enable both integration and automation is ensuring compatibility in process and hardware to realise the potential advantages. Identifying the most appropriate implementation of these individual processes to deliver the material and quality of data alongside the integration objectives is pivotal to the ultimate success of such a platform-based approach. It is now believed that methods in both chemistry and biology will facilitate this approach to yield a step change in the productivity in medicinal chemistry data generation2.
The emergence of flow synthetic chemistry3 as a discovery research tool over recent years provides an alternate environment for small molecule syn- thesis with potential advantages for a range of chemical transformations. Indeed future opportu- nities include miniaturisation at the microfluidic scale which offers further potential while still pro- viding more than adequate amounts of material for one or more in vitro bioassays.
Although typically undertaken in microtitre plate formats, a range of biological assays are now also feasible in a continuous flow format, indeed the concept of studying biochemical reactions in this flow format has been around for some consid- erable time4. Methods of detection demonstrated to date include mass spectrometry5, optical6 (eg fluorescence) and surface plasmon resonance. This approach will enable the integration of the biology with the chemistry, removing the somewhat oner- ous logistics requirements and allowing very rapid delivery of biological data for a newly-synthesised molecule, without the logistics overhead and hav- ing to resolubilise the test compound in aqueous buffers. This dramatic simplification, coupled with the potential advantages of speed accessible with an integrated and automated microfluidic
Drug Discovery World Summer 2011
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