5th July 2010:
Work Stream Five: Using Chemistry to Understand Biology
 |
The Question:To use the results of the whole cell screening of compounds for antimalarial activity as a way of gaining insights into the underlying targets of different drug classes and then use this information to identify novel targets. BackgroundIt is anticipated that within 2010 more than 5 million chemical entities will have been screened for antimalarial activity based on whole cell screens of P. falciparum malaria. The screens have included fully synthetic libraries (from both commercial sources and Pharma proprietary libraries) and natural product libraries. Activity has been established based on the ability to stop the growth of asexual P. falciparum malaria parasites over a 24- 48hr exposure period in vitro. The outputs of these screens will be placed into the public domain (e.g. the recent announcement from GSK, one of a number of companies who have submitted their library for screening as part of an initiative driven and financed by the Medicines for Malaria Venture [MMV]). |
Based on the success rates to date, there are likely to be more than 20,000 sub micromolar hits arising from these screens. The malaria genome contains about 5.5K genes of which less than 1% are likely to be druggable targets for chemotherapy. So we must conclude that many of the hits identified will be targeting the same process. In the coming year or so we expect that the stage specificity of these hits (i.e. activity against sexual stages and replicating and dormant liver stages) will be established, as will their in vitro cellular therapeutic indices, based on screens of representative mammalian cell lines.
The Challenge
The process of taking a screening hit and progressing it through the lead identification, optimisation, and candidate selection process is expensive and time consuming. It is questionable with current resources if a significant number of these screening hits can be progressed through this pipeline without some prioritization. Knowledge of mechanisms of drug action of these hits would significantly simplify prioritization. In addition this wealth of chemical information is a fantastic resource that should be used to provide insights into the biology of the malaria parasite and the essentiality of specific processes to parasite survival.
To view the minute of this workshop please click here