Researchers have uncovered how the frontline antimalarial drug, artemisinin, works and are now working on a promising chemotherapy-based compound to treat patients.
Scientists derived artemisinin from wormwood and developed the drug in China during Mao Zedong’s rule. It has saved millions of lives, but scientists are engaged in a constant game of cat-and-mouse with malaria, searching for ways to beat the parasite’s growing resistance.
Malaria claims the lives of about 440,000 people worldwide every year, the majority of whom are children younger than five years of age. Currently, artemisinin resistance has developed in South-East Asia and scientists fear it will soon reach Africa.
“If you’re going into a coma suffering very serious complications from malaria, you need immediate relief from the symptoms and this drug works very quickly,” says Leann Tilley, a professor and malaria researcher at the University of Melbourne.
But there are at least two catches.
First, artemisinin doesn’t work very well by itself. It effectively reduces the parasite’s impact, but doesn’t kill off every parasite infecting an individual. So it is always used in combination with other antimalarial drugs.
But here comes the second catch: resistance is rising to both artemisinin and the partner drugs.
“The combination of artemisinin and various partner drugs reduces the patient’s symptoms and stops them from dying, but no longer cures them. A few weeks later malaria comes back and the patient has to return for more treatment; but doctors are running out of treatment options,” Tilley says.
Degree of urgency
“Although we have very good scientists working on malaria, and we are making progress, there’s a risk that we could go backwards very quickly if resistance spreads to Africa,” Tilley explains.
It’s surprisingly common not to know exactly how and why a drug works. For example, the modes of action of paracetamol, which treats pain, and lithium compounds, which treat bipolar disorder, are not clear.
“When [artemisinin] gets inside the malaria parasite it goes off like a cluster bomb, damaging proteins.”
But not knowing how artemisinin works has been a block to understanding the growing resistance and to developing better treatments. Understanding the mechanism underpinning the drug’s action has become mission critical for malaria researchers.
“What we have discovered is that artemisinin packs a double whammy,” Tilley says. “When it gets inside the malaria parasite it goes off like a cluster bomb, damaging proteins.
“After the ‘explosion,’ the parasite is desperately reliant on shredder enzymes, called proteasomes, to dispose of the excess waste. Artemisinin also targets this waste disposal system, further weakening the parasite,” she says.
Knock out the shield
Blockage of the proteasome causes an accumulation of proteins that a “kiss of death” modification marks. When these damaged proteins build up, they stress the parasite and soon lead to cell death.
Tilley believes the parasite is becoming resistant to artemisinin by better shielding itself from the cluster bomb.
Here’s where chemotherapy comes in, because some cancer drugs are designed to attack proteasomes. They are called proteasome inhibitors.
Cancer cells grow at a gangbusters’ rate, creating so much waste they are more reliant on their proteasomes than regular cells, Tilley explains. Hitting cancer cells with proteasome inhibitors kills them.
So working on a hunch, Tilley tried hitting malaria parasites with proteasome inhibitors and discovered that artemisinin and the anti-cancer drugs can work together to knock out the proteasome and prevent the parasite’s “shielding” response.
Tilley has teamed up with pharmaceutical company Takeda of Japan and Swiss-based non-profit research foundation Medicines for Malaria Venture to discover a new parasite-specific proteasome inhibitor that works in tandem with artemisinin, and advance it to clinical trials.
Plan for resistance
The disease already debilitates malaria patients, so currently-used chemotherapy drugs could prove too toxic for them. That’s why the new modified drugs will have to only attack the malaria parasite’s proteasome, and not the patient’s, Tilley says.
“We want a compound that can be administered orally and will last a long time in the blood stream. If a suitable compound can be found, human trials could happen very soon,” she says.
And Medicines for Malaria Venture can shepherd promising antimalarial compounds through the pipeline from discovery to trial via a fast-tracked approvals process.
Developing a proteasome inhibitor antimalarial compound won’t solve the problem permanently, Tilley says.
“It’s inevitable that malaria will build resistance to the compound. You have to plan for the fact that resistance will develop.”
The research appears in Nature Communications.
Source: University of Melbourne
