Unmasking biological pathways for new anti-malaria drugs

Malaria parasites are growing increasingly resistant to anti-malaria drugs, with the current front-line drug, Artemisinin, showing signs of waning efficacy. 

But research undertaken in the Host-Pathogen Interaction group led by Professor Tania de Koning-Ward is building a strong understanding of the biological pathways that are essential to the survival of malaria parasites and using that knowledge to identify potential new anti-malaria drug targets.  

‘In the last decade, we have started to see patients who are not responding as quickly to treatment, which is indicating the beginning of resistance,’ Prof. de Koning-Ward says. 

‘It’s important that parasites that are developing resistance be tracked so we can see if resistance is spreading around the world. 

‘It’s only a matter of time before we lose our frontline anti-malaria drug and it is obvious that we just need this continual pipeline of anti-malaria drugs into the future so that when one treatment fails, we have another treatment option.’ 

Prof. de Koning-Ward’s group is part of a multi-disciplinary group of Australian researchers, funded by the National Health and Medical Research Council (NHMRC) Synergy scheme, that aims to optimise compounds that have come through drug screening programs for in vitro and in vivo safety and efficacy against malaria parasites. 

High throughput screening has identified a range of compounds that inhibit the in vitro growth of malaria parasites but further development of these compounds is limited by their lack of understanding of their biological targets, their mechanism of action as well as their demonstration of their selectivity and safety. Typically compounds require optimisation of chemical and pharmaceutical properties to achieve this. 

It is Prof. de Koning-Ward’s group who are deciphering the biological target of the compounds developed by its collaborators at Monash University. Her group is investigating the compounds’ mechanism of action and testing the efficacy of the compounds in in vivo models of infection.  

This research is a necessary part in finding the ‘chinks in the parasite’s armour’ and progressing ‘hit’ compounds to lead candidates for treating malaria. It will also determine the defined mechanisms of action of compounds and established safety and efficacy data that inform decisions on further development for clinical trials. 

‘One of the compounds that we’re testing targets a parasite enzyme involved in haemoglobin digestion,’ Prof. de Koning-Ward says. 

‘The parasite lives inside red blood cells and digests the haemoglobin to provide the amino acids that it requires for growth. 

‘One of the drugs is hitting one of the enzymes in that haemoglobin degradation pathway. If you can block the parasites from getting the amino acids from haemoglobin digestion, then you essentially starve them, and they die.  

‘What we are making sure is that that drug is hitting that particular pathway and not something else.  And making sure that we know what the target is, and not hitting a host target because that would be toxic to humans.” 

Part of this work includes getting a full picture of how successful this drug may be in the field by investigating whether the parasite can generate resistance to the compound in the lab, which may happen if a patient does not take the right dose of the drug.  

Another focus of Prof. de Koning-Ward’s research program is to dissect how the parasite remodels its host cell. 

‘It is like the parasite renovates its home – it creates a viable place for it to thrive and evade the host system,’ Dr de Koning-Ward says.  

‘We now know some of the key molecular pathways to do that. And now we’re trying to screen for compounds that block these processes because we know that is such a fundamental part of a parasite’s survival. If they can’t renovate that host-cell, then they can’t cause disease and they can’t evade the immune response.’ 

The drug that targets haemoglobin digestion is steps close to pre-clinical trials but with thousands of compounds to work through there are many more drug screens for other pathways being completed by the group based at IMPACT. 

Prof. de Koning-Ward says the project has really enabled the group to collaborate with a range of researchers with diverse expertise. 

‘It’s really important that you use other people’s skillsets because I think you can go a lot further,’ she says. 

‘Structural biologists and chemists, parasitologists and cell biologists have all come together. And that’s been really, really good. It has been a multidisciplinary effort.’  

This piece is a real-world impact article that was recently published in our Annual Report. Interested? Read the full report here