MRC researchers achieve a significant hit-rate when using screening compounds in a novel high throughput screening (HTS) assay designed to identify potential anti-malaria agents
Researchers in the assay development group at Medical Research Council Technology and the MRC National Institute for Medical Research have achieved a significant hit-rate when using Maybridge screening compounds in a novel high throughput screening (HTS) assay designed to identify potential anti-malaria agents.
Widespread resistance to current anti-malarial drugs has created an urgent need for effective new compounds and subtilisin-like proteases have been identified as a potential therapeutic target for drugs designed to disrupt the life cycle of the malaria parasite (Plasmodium falciparum ).
The novel fluorescence-based assay developed by Dr M Blackman and his colleagues uses a synthetic peptide substrate for a recombinant malaria protease, which is labelled at its N- and C- terminal ends with tetramethylrhodamine (TMR).
Working closely with MRCT's assay development group the bench assay was converted into a high throughput screen and implemented on a Beckman FX liquid handling robot.
After screening 10,000 randomly selected compounds drawn from Maybridge's 53,000-strong screening compound library, the researchers had a hit rate of 0.66%. Confirmed hit compounds were readily re-supplied from Maybridge and used in for further target validation in Dr Blackman's group.
Hits showed good selectivity for the target protease when tested against a range of mammalian and bacterial serine proteases.
Three of these compounds are structurally related and kill blood-stage malaria parasites.
"We believe that these compounds are a good starting point for anti-malarial drug discovery" said Michael Dalrymple, director of applied research at MRCT.
"This project is a tripartite interaction between MRC scientists, Maybridge, and MRCT.
The work of MRCT's assay development group has enabled MRC research to move closer to a practical application.
There are a number of other such projects in our pipeline which will utilise the Maybridge compound collection and we value this interaction.".
