Tuesday, August 26, 2014

Application: High throughput screening assay to identify anti-malarial drugs

Malaria is a parasitic disease spread through mosquitos. It is widespread in many areas with poor access to good quality medical care, and is one of the most devastating diseases on the planet, often leading to coma or death. In fact, the World Health Organisation estimate that in 2010, the disease killed between 660,000 and 1.2 million people (1). Although anti-malarial drugs are available, resistance to these is increasing, with potential impact on the health of millions of people, as well as having a major negative effect on the economies of those countries affected.

A family of ATP dependent plasma membrane pumps have been implicated by Genome Wide Association Studies to have roles in a variety of different conditions. One particular member of this family (PMCA4) has been shown to be associated with resistance to malarial infection. Due to the wide ranging effects of the PMCA family, a group in Manchester devised an assay to screen for potential drugs targeting this group of proteins, using PMCA4 as a model (2).

To do this, they used the CisbioTranscreener assay which uses FRET technology in combination with long lived fluorophores to assay for ATPase activity with a Z’ of greater than 0.5.  Using this assay, over 20,000 compounds were screened in a single day using the FLUOstar OMEGA, leading to nearly 1500 compounds that inhibited PMCA4 activity by more than 50%.
The Cisbio Transcreener assay used to identify drugs that target PMCA4
was detected with the FLUOstar OMEGA from BMG LABTECH

Although it is very early days in the drug discovery process, someday a descendant of one of these compounds may have an application as an anti-malarial treatment, bringing potential relief to millions of people.

  1.  NayyarGML, Breman JG, Newton PN, Herrington J (2012). "Poor-quality antimalarialdrugs in southeast Asia and sub-Saharan Africa". Lancet InfectiousDiseases 12 (6): 488–96.
  2. Mohamed TM, Zakeri SA, Baudoin F, Wolf M, Oceandy D, Cartwright EJ, Gul S, Neyses L (2013). “Optimisation and validation of a high throughput screening compatibleassay to identify inhibitors of the plasma membrane calcium ATPase pump--anovel therapeutic target for contraception and malaria”. J Pharm Pharm Sci 16 (2): 217-30