New target for malaria

03 September 2019

Interview with 

Andrew Tobin, University of Glasgow

MOSQUITO

MOSQUITO

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Every year malaria kills nearly half a million people, most of them children. The cause is the plasmodium parasite transmitted by mosquito bites. Unfortunately, the parasite is rapidly becoming resistant to our current anti-malarial drugs. Now, scientists have uncovered a vulnerability in the parasite that can stop it in its tracks. It’s a crucial molecule - called protein kinase PfCLK3 - that’s essential to the parasite. Andrew Tobin and his team at Glasgow University have found a way to block it, and he spoke to Katie Haylor...

Andrew - The world does have very effective treatments, and those treatments have seen a reduction in the amount of malaria in the world. However, the parasite is able to adapt. We're seeing evidence of resistance to the current frontline treatments. We need new medicines with new molecular mechanisms of action.

Katie - Tell us about this treatment then, how does it work compared to the treatments we've already got?

Andrew - This treatment targets a very specific protein in the parasite which is essential for the parasite to survive. This protein is involved in producing the messenger molecules that make other proteins. Your protein is encoded on DNA. You need to transfer that code in order to get converted into protein and that's done using a molecule called RNA. But the RNA needs to be chopped up before it can effectively be used to make protein. Our target is involved in cutting up that RNA and by interfering with that process we stop essential proteins being made in the parasite. We’ve picked protein kinase PfCLK3 because we suspected that this protein kinase needed to be active in multiple stages of the parasite lifecycle. So by inhibiting our protein kinase, we prevent essential production of proteins and have therefore a very effective medicine for malaria.

Katie - How do you know that this works?

Andrew - Firstly you need to make sure that it works in the test tube against your target. Does it kill real malarial parasites which we culture in the lab here in Glasgow. It kills the parasite. Now you've got to know whether or not the different stages of the parasite lifecycle are killed, and then you've got to ask the question: can you actually cure an animal that's infected with malaria. And we go to a mouse model there to see if our compound can prevent the infection of the parasite in the mouse model. And finally we asked the question whether or not our inhibitor can stop insects from being infected and therefore be a transmission blocker as well as a cure. And it does. Treating the mouse with our compound prevented the mice from contracting mouse malaria. And remarkably, and these are extraordinary experiments because you have to feed mosquitoes with red blood cells that have been infected with the malaria parasite. And we find that by treat in the blood before the insect feeds on the blood, we can prevent the insect from becoming infected with malaria.

Katie - And that stopped transmission.

Andrew - That did indeed. And so that's a really critical experiment because if you want to eradicate malaria you need to prevent the transmission through the insect.

Katie - You need to get it into humans though I imagine next, so how do you envision that happening?

Andrew - The way that you do that is to now take your current drugs and develop them so that they become more effective but importantly they become safe for human use. And so we have a pipeline of experiments now involving all the major players in the drug discovery area: the Bill & Melinda Gates Foundation, Medicines for Malaria Venture, Malaria Drug Accelerator. These organizations will help us refine this drug optimize this drug and develop it for human use.

Katie - The problem is, there's a new drug, then the microbe genetically changes to counter that drug. Aren't you going to run into the same problem with this?

Andrew - I don't see there's any question that the parasite will become resistant to our new drug. This is why antimalarials are given in combination. But even then, resistance still develops and we will just need a new drug after a while.

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