Stained malaria infected red blood cells (brown) show parasites in various stages of development (purple). [By Lukas.S at en.wikipedia, from Wikimedia Commons]
Stained malaria infected red blood cells (brown) show parasites in various stages of development (purple). [By Lukas.S at en.wikipedia, from Wikimedia Commons]

In the third century AD, Quintus Serenus Sammonicus, who was the physician to the Roman emperor Caracalla, presented the city with its first antimalarial “remedy.” In his medicinal philosophy poem Liber Medicinalis, Sammonicus advised that protections from malaria could be obtained by simply wearing an amulet inscribed with the incantation Abracadabra—a word which has now become synonymous with cartoon wizards and children’s starter magic kits.

Needless to say, Sammonicus’ cure was ineffective, as malaria rates swelled to epidemic levels by the end of the Roman Empire and still continues to represent a global health threat. Thankfully, over the years scientists have had more precise methods of combating malaria through medication and insecticides, but resistance by the malaria parasite is ever present.

Now, researchers from the Medical Research Council's (MRC) Toxicology Unit at the University of Leicester and the London School of Hygiene & Tropical Medicine have discovered new ways in which the malaria parasite is able to survive within the host.  

“This is a real breakthrough in our understanding of how malaria survives in the blood stream and invades red blood cells,” stated senior author Andrew Tobin, Ph.D., professor in the MRC Toxicology Unit at the University of Leicester. “We've revealed a process that allows this to happen and if it can be targeted by drugs we could see something that stops malaria in its tracks without causing toxic side-effects.”

The findings from this study were published recently in Nature Communications through an article entitled “Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion.”

Using a mixture of chemical and genetic tools, combined with the power of phosphoproteomics, the investigators were able to identify an essential cGMP-dependent protein kinase, called PfPKG, which is part of a major intracellular signaling hub involved in a number of core parasite processes that include proteolysis, gene regulation, cell invasion, and egress. 

“It is a great advantage in drug discovery research if you know the identity of the molecular target of a particular drug and the consequences of blocking its function,” said David Baker, Ph.D., Malaria Centre Head of Biology at the London School of Hygiene & Tropical Medicine and co-senior author on the study. “It helps in designing the most effective combination treatments and also helps to avoid drug resistance which is a major problem in the control of malaria worldwide.”

The researchers were able to do an extensive evaluation of PfPKG in the malaria parasite species P. falciparum, identifying key regions of the enzyme’s structure that could be inhibited by various novel compounds they designed. Through their inhibition studies, the scientists were able to identify a number of PfPKG-dependent phosphoproteins that were involved in parasite egress, invasion, and calcium signaling—all of which are being evaluated as possible therapeutic intervention points. 

“Tackling malaria is a global challenge, with the parasite continually working to find ways to survive our drug treatments,” explained Patrick Maxwell, Ph.D., chair of the MRC's Molecular and Cellular Medicine Board. “By combining a number of techniques to piece together how the malaria parasite survives, this study opens the door on potential new treatments that could find and exploit the disease's weak spots but with limited side-effects for patients.”

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