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Close-up view of malaria proteins could yield possible targets for new treatments

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By Sharon Kingman
Staff Writer

LONDON – An eight-year study that involved sifting the genome of the malaria parasite has delivered a list of proteins that the parasite cannot do without – as well as determining at what point in the parasite's life cycle each of the proteins is expressed.

The list will make it possible for drug developers to decide which parasite proteins may make good targets for new drugs that aim to treat malaria and/or prevent its transmission by the mosquito.

The study, published in Cell Host & Microbe, complements an earlier publication in the same journal by the same team. Together, they provide an all-around view of proteins that play important roles in regulating many cellular processes during the development of the malaria parasite.

Rita Tewari, associate professor of molecular cell biology at the University of Nottingham in Nottingham, UK, told BioWorld Today: "Our work has allowed us to identify those genes which are and those genes which are not crucial for the parasite to grow and, in particular, at which part of the life cycle it is essential for these genes to be expressed. We can use this knowledge to develop new drugs or vaccines that will stop the parasite growing in humans or in mosquitoes and so stop this disease."

Tewari and her collaborators reported their findings in a paper in the July 9, 2014, issue, titled "Genome-wide Functional Analysis of Plasmodium Protein Phosphatases Reveals Key Regulators of Parasite Development and Differentiation." The first author is David Guttery, who is now at the University of Leicester. Collaborators included the Medical Research Council's National Institute for Medical Research, Oxford University, Imperial College London and King Abdullah University of Science and Technology, Saudi Arabia.

For the study, Tewari and her team examined the genome of Plasmodium berghei, the parasite that causes malaria in rodents. The genome of P. berghei is very similar to that of Plasmodium falciparum, the main parasite that causes malaria in humans.

At the beginning of her research program, Tewari decided to focus on genes encoding enzymes that help to regulate cellular metabolism in P. berghei. Those enzymes include two main types, known as kinases and phosphatases.

The kinases are responsible for adding phosphate groups to other proteins, normally in order to activate those proteins. By contrast, the phosphatases perform the opposite role: They remove the phosphate groups once the phosphorylated protein has carried out its function.

Tewari and her colleagues reported in 2010 that they had identified 72 kinases in P. berghei; in the paper in Cell Host & Microbe, they described a list of 30 protein phosphatases.

"Importantly, our study also indicates which of these phosphatases are important in the different stages of parasite development," Tewari said. "We found that 16 of these 30 protein phosphatases are important for the blood stage in the mammal – which is what causes the symptoms of the disease."

When they looked at the other 14, they found that eight were not essential for the parasite's survival and reproduction; when they knocked out any one of those eight genes, the parasite could still successfully complete its life cycle. "So we know that these proteins are not good targets for future drugs," Tewari said. "Either the parasite does not need these proteins or it can compensate for their absence in some way."

Another six protein phosphatases remain, which the parasite requires in order to survive in the mosquito host, she said. Comparison with the human genome also has shown that among the genes that are crucial for completion of the P. berghei life cycle are some that do not appear at all in the human genome. "These will be the good ones to focus on for future drug development," Tewari said.

Tony Holder, head of the Division of Parasitology at the Medical Research Council's National Institute for Medical Research, said: "Inhibitors of protein kinases are already used extensively 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 by the mosquito."

The team is now looking for partners to help develop its findings. "We now want to identify the molecules with which these enzymes are interacting, in order to determine good drug targets," Tewari said. "We will then look to see if we can find small molecules that will be able to interfere with that interaction. We plan to collaborate with chemists, carry out molecular modeling and screen compound libraries in order to find good candidate drugs."

She and her group already have published papers examining the functions of two unique protein phosphatases, PPKL and SHLP1, which could help in the design of new drugs to treat malaria.

Earlier this year, Tewari and others also reported in Nature Chemistry on their work on N-myristoyltransferase as a possible therapeutic target in malaria.