In an infected patient a small proportion of parasites form gametocytes, the sexual form of the parasite. It is these gametocytes, taken up by the mosquito when she feeds, that ultimately allow the parasite to infect the next person. In collaboration with partners (Imperial College London, GSK, Radboud University, the Netherlands and Griffith University, Australia) MMV has developed a range of tools to screen and identify compounds with activity against gametocytes. These tools have enabled us to identify a number of interesting molecules that not only target the blood stage of the lifecycle but the sexual stages as well. To ensure the pipeline remains populated the hunt is on to discover further compounds with such dual activity.
1. How does the assay work?
The assay is based on imaging technology. We use 384-well microtiter plates; each well contains cultured gametocytes which express fluorescent proteins. A green protein identifies the parasite, while red tells us whether it’s alive. We can determine that the parasite is a late-stage gametocyte by its shape. We then add compounds to the wells and assess their effect on the cells by studying changes in the parasite florescence.
2. What is different about your approach?
The screening technology we use is based on state-of-the-art imaging technology and so is incredibly information-rich. We are looking at the whole parasite in one go rather than a simple target, as with other screening technology. It’s the difference between having a tractor and a Ferrari!
3. What has been achieved so far?
We have a late-stage gametocyte assay up and running. Using the assay we have started to screen the 25,000 compounds known to be active against blood-stage malaria. The preliminary data generated is very exciting and there are already plans to screen many more compounds. We aim to screen 250,000 compounds this year.
4. What value has MMV added to your work?
Working with MMV has provided me with the opportunity to focus on an area of drug discovery I otherwise wouldn’t be able to. It means I can bring the skills I have developed in pharma and academia to an issue that needs to be addressed. I enjoy coming to meetings at MMV as I interact with and learn from people who work across the whole pipeline. Working with MMV has also opened doors to people doing research that is similar or complementary to mine.
Vicky Avery is the Chief Investigator & Head of Discovery Biology at Griffith University, Australia.