Creating a new drug to beat a devastating disease like malaria is a case of try, try and try again.
Burnet’s Gilson/Crabb Group Co-Head, Dr Paul Gilson is one of many scientists across the globe working to overcome this mosquito-borne disease which kills more than 430,000 people a year, mostly young children, and imposes debilitating effects on another 216 million.
While there is competition between scientists to attract funding, the greatest urgency comes from the disease itself. In parts of Asia, malaria is growing resistant to the current front-line antimalarial drug, artemisinin.
“It’s very important to find an alternative to artemisinin because it is going the way of a lot of older generation antimalarials where the parasites are now very resistant,” Dr Gilson said.
“This is happening in Thailand and Cambodia in Southeast Asia, where the half-life of a parasite - the time taken to clear the parasites - is increasing.”
And it’s a long road to create a new effective drug.
“The reality is that most drug projects never result in something that reaches the clinic. It’s the same across the drug development world - most don’t make it out of the lab because of issues such as toxicity,” Dr Gilson said, in his Burnet laboratory in Melbourne.
“At Burnet we have a number of projects, hoping that maybe one of them will get through.”
Image: A malaria parasite (green) invading a red blood cell.
Three Burnet antimalarial research projects
The most advanced project is called WEB, (a condensation of Walter and Eliza Hall Institute, the project’s main collaborator, and Burnet) and is a series of compounds that have been under development for over seven years.
“With the WEBs, we’ve reached a level of potency about the same as chloroquine, which is an antimalarial that was widely used but now there’s a lot of resistance to it,” Dr Gilson said.
“We’ve got funding to develop WEB further and eliminate some side effects - that’s underway at the moment.”
The other challenge is to identify the target of these WEB compounds and how they work; information which is currently unknown.
Other Burnet antimalarial projects include a drug that targets an enzyme called a kinase that has a role in invasion.
“Every 48 hours the parasites burst out of an old red blood cell and go and invade a new one and they replicate quite quickly. This invasion process involves an enzyme called protein kinase A and we’re interested in developing a drug that can block that kinase,” Dr Gilson said.
A third project in development involves research to stop parasites taking up nutrients from blood plasma.
The group have been screening the MMV Malaria Box, a set of 400 compounds whose targets are unknown, made available by international group the Medicines for Malaria Venture to scientists around the world so they can try and discover the compounds' targets.
“We got that box and we were screening for drugs that block the ability of parasites to take nutrients up from the blood plasma,“ Dr Gilson said.
“We discovered two compounds that were reasonably good at blocking the parasite’s ability to take up nutrients.”
However, while the drugs were more effective at blocking nutrient uptake this did not translate into improved parasite killing. Therefore this particular project will be written up as research, rather than advancing to directly save lives.
Years of trial and error all part of the scientific journey
Are outcomes like this frustrating, after sometimes years of work?
“It can be frustrating when you get a long way down the track with a drug you think is going to work and then something happens to condemn it to the scrap heap, but that’s the way science works,” Dr Gilson said.
“There’s a lot of hits and misses with this sort of thing.”
However it’s not time wasted – many failed antimalarial drugs go on to have lives as useful research compounds in laboratories, as well as adding to the body of knowledge about malaria parasitology.
So are scientists around the world competing or collaborating to create an effective antimalarial?
“Both. If you’re going to secure grants there has to be a point of difference between you and other people. It’s probably competitive at the earlier stages until it gets to the pre-clinical stage and then there is more collaboration.”
Finding an artemisinin alternative is not just needed to combat the partial resistance already seen in Southeast Asia, but to provide a cheaper drug. It’s also important to combine artemisinin, which is rapidly eliminated from the body, with a long-acting drug partner drug to mop up the few parasites left behind.
Read more here about Burnet’s work developing antimalarial and other medications.
Burnet is proudly supporting the 1st Malaria World Congress in Melbourne from 1-5 July featuring experts across research, policy, public health, international development and advocacy focused on eliminating malaria.