Protein phosphatase study brings malaria drug targets a step closer

09 July 2014

Ookinetes, the fertilised form of the malaria parasite in a mosquito’s body.

Image: Ookinetes, the fertilised form of the malaria parasite in a mosquito’s body.

Scientists searching for new drug and vaccine targets to stop transmission of one of the world's deadliest diseases believe they are closer than ever to disrupting the life cycle of this highly efficient parasite.

The findings come from research into the roles played by protein phosphatases - enzymes that act as 'on' and 'off' switches for proteins - as the malaria parasite develops in the body and then in the mosquito gut.

The research was led by the University of Nottingham in collaboration with the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute), together with colleagues at Oxford University, Imperial College London and King Abdullah University of Science and Technology, Saudi Arabia.

Dr Rita Tewari of the University of Nottingham said: "This latest study identifies how protein phosphatases regulate parasite development and differentiation. Our research provides a systematic functional analysis for all the 30 phosphatases in Plasmodium berghei - the parasite responsible for causing malaria in rodents. These enzymes work in tandem with the protein kinases identified by the same team in a complementary study carried out in 2010. If we can find out what proteins are essential for these parasites to develop and divide, maybe we can target those proteins and arrest them with drugs or vaccines."

Dr Tony Holder, Head of the MRC-NIMR Division of Parasitology, said: "Inhibitors of protein kinases are already used in treatments for other diseases and there is growing interest to develop phosphatase inhibitors as drugs. Identifying the key kinases and phosphatases in the parasite life cycle will define the targets for drug development to treat human malaria and prevent its transmission in communities by the mosquito."

Using a number of molecular cell biology and biochemical techniques, Dr Tewari and her team found that half the phosphatase genes could not be 'knocked out' suggesting some of these genes could be future drug targets as their presence is critical to parasite growth. 

Six of these genes were found to be crucial for sexual development and hence could be drug targets for parasite transmission to and from the mosquito. This research, using the mouse malaria parasite, can be directly related to the human malaria parasite, as many of the genes share a very similar homology and symptoms of the diseases are very similar.   

Dr David Guttery, now at the University of Leicester, said: "Building on our previous research on the protein kinases, this study represents a complementary view of the protein phosphorylation mechanism and gives us tantalising clues to the major players in this pathway. It will be exciting to see in the future which proteins are targeted by the protein kinases and phosphatases, and whether they act upon each other too."

The paper, Genome-wide functional analysis of Plasmodium protein phosphatases reveals key regulators of parasite development and differentiation, is published in Cell Host and Microbe.

  • New research into malaria enzymes called protein phosphatases brings scientists a step closer to being able to disrupt the life cycle of the malaria parasite and finding a way to stop transmission of the disease. 
  • Protein phosphatases are crucial for many stages of the malaria parasite life cycle and play key roles in regulating many cell processes. 
  • Malaria remains one of the most deadly scourges of the developing world - killing up to one million people and causing clinical disease in 300 to 500 million people every year. In humans the deadliest form of malaria is caused by the single cell parasite Plasmodium falciparum. Disrupting its life cycle could save the lives of millions of people.