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London School of Hygiene & Tropical Medicine Malaria Centre

Blog | Could this be a next-generation antimalarial drug?

05 September 2017
Blog | Publication

 

New antimalarial drugs are urgently needed because resistance has developed against most, if not all, of those currently in the clinic. Although there are some interesting candidates in the drug discovery pipeline, the rate of attrition is high and so new possibilities must be explored to ensure we have future tools for malaria elimination programmes. Professor David Baker, from the London School of Hygiene & Tropical Medicine, and his collaborators have just published a research article in the journal Nature Communications that describes a compound which works in a unique manner compared to current antimalarial drugs.

 

New chemical to block malaria parasite development and transmission

 

The publication shows that, apart from clearing blood stage parasites (that give you the disease), the compound also blocks transmission to mosquitoes by interfering with gametocyte development; a relatively rare property for antimalarial drugs. The compound is also shown to bind to and inhibit a protein kinase known as PKG, which no current antimalarial drugs do. David’s group have previously shown that PKG is essential for gametocyte and blood stage parasite development. As no previous, or current, antimalarial drugs target PKG you would expect drug-resistant malaria parasite populations in the field to be fully susceptible to a PKG inhibitor, and if shown to be successful, a PKG inhibitor could be used as a component of a new type of antimalarial drug combination.

 

It should be emphasised that the PKG inhibitor the London School of Hygiene & Tropical Medicine have developed, through partnership with MRC Technology (now called LifeArc), is an early lead compound. This means that it requires optimisation of some of its properties before it could be considered for human trails, and if proved safe it will still be several years before it could be approved for widespread use.

 

What next?

 

By demonstrating the properties of this compound, Professor Baker has achieved financial support from the Tres Cantos Open Lab Foundation (which employs three postdoctoral researchers at Tres Cantos, in Spain) to further explore PKG as an antimalarial drug target.

 

Publication overview

 

The paper describes the characterisation of a new antimalarial lead compound that targets a protein kinase enzyme (the cGMP-dependent kinase, PKG). This lead compound:

1. Kills blood stage malaria parasites (which cause disease), but also,

2. Blocks the development of the sexual stage parasites (which mediate malaria transmission).

 

Importantly, in addition to showing in vitro data (cellular research) the article also provides in vivo (whole animal research) proof-of-concept data that demonstrates one of the lead compounds reduces parasite burden to undetectable levels in a mouse model of the human malaria parasite Plasmodium falciparum. X-ray crystallography data is also presented, which shows how this inhibitor interacts with the malaria parasite PKG enzyme. ‘Since no existing antimalarial drug targets the PKG enzyme, we would expect this class of inhibitor to be effective against drug resistant parasite populations’. [Professor Baker]