A team of researchers from the US, UK and Australia has developed a class of drugs, which they hope can complement the current standard anti-malarials, Artemisinins, and restore their activity in drug resistant parasites.
Isolated from the plant Artemisia annua, or sweet wormwood, Artemisinins are very effective medicines for people infected with Plasmodium falciparum, the most deadly malaria parasite killing half a million children every year.
Discovered by Chinese Tu Youyou, who was awarded the Nobel Prize in Medicine in 2015, their use spread quickly because of their level of efficacy and tolerability.
However, in some countries of South-East Asia malaria parasites have been found that are able to cope with the treatment - and scientists fear that the Artemisinins resistance could soon spread to Africa where most of malaria-related fatalities occur.
In response to the threat, the World Health Organisation now recommends to use combinations of Artemisinins with other drugs as first-line treatment of malaria.
Described in Nature and co-authored by Melbourne University's Professor Leann Tilley, the new drugs target the parasite's waste disposal system, the proteasome.
“The parasite’s proteasome is like a shredder, that chews up damaged or used-up proteins. Malaria parasites generate a lot of damaged proteins as they switch from one life stage to another and are very reliant on their proteasome, making it an excellent drug target,” Prof Tilley said in a university statement.
However, compounds previously found to inhibit the parasite proteasome also reacted with the human proteasome, and hence were too toxic to be used as therapeutic agents.
To overcome this problem, researchers at Stanford University purified the proteasome from the malaria parasite and examined its activity against hundreds of different peptide sequences using a novel method developed at the University of California, San Francisco. Using this information, they designed inhibitors that selectively targeted the parasite proteasome, while sparing the human host enzyme. This high degree of selectivity allowed the Stanford team to confirm that the drug could be used to clear parasites from infected mice.
Through a relatively new technique called Single Particle Cryo-Electron Microscopy, scientists at the MRC in Cambridge were able to generate a three-dimensional, high-resolution structure of the parasite proteasome bound to the inhibitor, and they made similar observations with the human enzyme. Using this information they were able to deduce why the drug is only reacting with the parasite protein.
It is the first time that the technology has been used to gain such information.
The authors made another important observation: the potency of the new anti-proteasome drugs is much stronger when they are used in combination with Artemisinins, and Professor Tilley found that this is also the case in parasites that have developed resistance to Artemisinins.
“The new proteasome inhibitors actually complement artemisinin drugs,” Prof Tilley said. “Artemisinins cause protein damage and proteasome inhibitors prevent the repair of protein damage. A combination of the two provides a double whammy and could rescue the artemisinins as anti-malarials, restoring their activity against resistant parasites.”
Prof Tilley and her team are currently working with experts from Japanese anti-cancer drug giant Takeda Pharmaceutical Company Limited and Swiss-based foundation Medicines for Malaria Venture to identify additional classes of parasite specific proteasome inhibitors that could be advanced to clinical trials. She recently received $297,000 from the Global Health Innovative Technology Fund to conduct this work.
“The next step is screening the Takeda libraries to find a similar drug that doesn’t affect the human proteasome. The current drug is a good start but it’s not yet suitable for humans. It needs to be able to be administered orally and needs to last a long time in the blood stream.”
Prof Tilley said if they can find an existing drug in Takeda’s drug libraries that matches the structure of the new malaria drug, they could move it towards human trials very quickly.
More information: www.uq.edu.au