New drug target stems from malaria enzyme discovery

12 December 2013

Anopheles gambiae mosquito

Image: Anopheles gambiae mosquito©  US Centers for Disease Control and Prevention.

An enzyme of the malaria parasite Plasmodium that's important in the blood stage of the disease also plays a key role in the asymptomatic liver phase, making it a good target for new drugs.

The enzyme, called SUB1, has previously been implicated in releasing the parasite from infected red blood cells. Now, scientists at the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute) and the Wellcome Trust Sanger Institute have discovered it's also involved in the liver phase of disease.

When a person is bitten by a mosquito infected with Plasmodium, forms of the parasite called sporozoites are released into their bloodstream, where they travel to the liver and invade liver cells. Each sporozoite then replicates many times, producing thousands of parasite cells called merozoites. These are released back into the host's bloodstream to start the blood stage of the life cycle, which is responsible for all the clinical symptoms of the disease.

Professor Mike Blackman of the NIMR explained: "Growth of malarial liver stages represents a massive expansion of the transmitted parasite infection and is crucial for disease progression. In this study, we have shown that a parasite enzyme previously thought to play a role primarily in development of blood stages is also indispensable for development in the liver."

The scientists used a technique called 'recombineering' alongside a gene deletion strategy to investigate the effect of completely disabling the SUB1 gene in the parasite's liver stages.

They found that SUB1 is not required for the early stages of growth inside liver cells, but is essential for development of liver stage schizonts (the lifecycle stage in between sporozoites and merozoites), as well as for the production of mature liver merozoites.

Dr Catherine Suarez, also of NIMR, said: "Our results show that, as well as potentially preventing growth of blood-stage parasites that cause disease, inhibitors of SUB1 could be used in preventative approaches to control the clinically silent liver stage of the malaria parasite life cycle."

Professor Blackman added: "We know from previous work that SUB1 in the malaria parasite is a 'druggable' enzyme; that is, it can be accessed and inhibited by small compounds that have potential to be developed into drugs. Our new findings raise the possibility of developing drugs that block the development of a malarial infection well before it progresses to the point where it begins to cause clinical disease."

The paper, The malarial serine protease SUB1 plays an essential role in parasite liver stage development, is published in PLOS Pathogens.

  • An enzyme involved in the blood stage of malaria is also crucial to the liver stage of infection, according to new research.
  • This makes it a good target for much-needed new preventative drugs, particularly as the liver stage of the disease is completely asymptomatic - meaning that an infection could be blocked before it causes clinical disease.
  • Malaria remains one of the most devastating diseases in the developing world - one report showed it caused 1.2 million deaths in 2010 alone, mostly in children aged under five. The most commonly used drugs are failing rapidly due to resistance, alternatives are expensive and there is no vaccine.