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If you gum up a malaria parasite’s protein-chewing machine, it can’t do the things it used to do

"Life in the tropics" evokes images of rain forests, palm trees, tamarinds and toucans. It also has a downside. To wit: One-third of the Earth’s population - 2.3 billion people - is at risk for infection with the mosquito-borne parasite that causes malaria.

Thankfully, mortality rates are dropping because of large-scale global intervention efforts. But malaria remains stubbornly prevalent in sub-Saharan Africa and Southeast Asia, where hundreds of millions of people become infected each year and more than 400,000 of them - mostly children younger than 5 - still die from it.

The parasite has the knack of evolving rapidly to develop resistance to each new generation of drugs used to fend it off. Lately, resistance to the current front-line antimalarial drug, artemisinin, is spreading and has now been spotted in a half-dozen Southeast Asian countries.

So it's encouraging to learn that Stanford drug-development pioneer Matt Bogyo, PhD, and his colleagues have designed a new compound that can effectively kill artemisinin-resistant malaria parasites. Better, exposure to low doses of this substances re-sensitizes them to artemisinin.

By exploiting tiny structural differences between the parasitic and human versions of an intercellular protein-recycling machine called the proteasome, the compound Bogyo's team has created attacks the malaria parasite while sparing human cells.

Proteasomes abound in every human cell as well as in the one-celled infectious parasites responsible for malaria. These barrel-shaped clusters of proteins make their living by chewing up other proteins and are crucial not only to the elimination of faulty proteins but clearance of proteins that, while viable in themselves, are interfering with critical time-dependent processes such as cell replication. So clogging proteasomes' function wreaks havoc within a cell.

But compounds previously found to block proteasome activity in the malaria parasite have also tended to inhibit the human version of the proteasome, resulting in toxicity that would be unacceptable in a malaria drug.

But in a study published in Nature, Bogyo and his Stanford associates teased apart minute structural differences between malaria-parasite and human proteasomes and designed a compound tailored to gum up the parasite's proteasomes but not ours. Then, with help from scientists at the University of Cambridge and the University of Melbourne, they showed that it worked, and why.

In fact, the compound actually seems to be even more efficacious against artemisinin-resistant parasites, whose proteasomes have to be in top working condition in order to fend off the protein-warping effects of that drug. Here's how Bogyo put it when I interviewed him for my news release about the study:

The compounds we’ve derived can kill artemisinin-resistant parasites because those parasites have an increased need for highly efficient proteasomes. So, combining the proteasome inhibitor with artemisinin should... allow the continued use of that front-line malaria treatment, which has been so effective up until now.

Previously: Why C. difficile-defanging mouse cure may work in people, too, Compound clogs Plasmodium's in-house garbage disposal, hitting malaria parasite where it hurts and Nervous breakdown: Preventing demolition of faulty proteins counters neurodegeneration in lab mice
Photo by Chelsea Nesvig

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