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Pair of pipsqueak proteins punch malaria parasite where it hurts most: its proteasome

The parasite that causes malaria is remarkably adept at developing resistance to the drugs devised to combat it. But new research suggests a solution.

The one-celled parasite, or protozoan, that causes malaria is remarkably adept at developing resistance to the drugs devised to combat it.

With 40% of the world's population at risk for contracting malaria, some 220 million new cases annually and close to half a million deaths per year -- mostly kids less than five years old -- any drug that can get a handle on this profoundly pathogenic pest is worth paying attention to.

And here comes Stanford drug-designer/researcher Matt Bogyo, PhD, with a vice grip in his hand. In collaboration with researchers at Columbia University, Bogyo reports in the journal PLoS Pathogens that a pair of peptides -- pipsqueak proteins -- may be able to put the squeeze on the parasite, formally known as Plasmodium falciparum.

Unlike the one-celled organisms with which we're most familiar -- bacteria -- protozoans are biologically quite similar to us humans (and everything in between) when it comes to the standard equipment residing inside our cells. We just happen to have a lot more of the cells, by a factor of... oh, about 37.2 trillion by one rough estimate.

The inside of a bacterial cell is very simple -- pretty much just a long strand of DNA floating around in a protein-rich soup.

But from protozoans on up, a cell's innards include lots of prettily packaged machinery, collectively called organelles. These include, for example, mitochondria, believed to have originated as bacteria themselves, who found an easy meal ticket by cutting a deal with our one-celled progenitors, whoever those were, by which the mitochondria supply power in exchange for food.

Another key organelle found in every single cell in every one of us multi-celled creatures, and in protozoans as well, is the proteosome: effectively a garbage disposal geared to slicing and dicing used-up proteins so their building blocks can be recycled into shiny new proteins.

All proteasomes are pretty much alike, but it turns out there are a few subtle differences between ours and P. falciparum's: same make, different model. Different enough from ours that Bogyo has been able to design drugs that can plug up the protozoan's proteosome without gumming up our own.

That's a big deal, because a malaria parasite with a plugged-up proteasome can't accomplish jack squat. Bogyo and his colleagues have designed two peptides that do just that. Remarkably, not a single strain of the bug they tested developed resistance to both. In fact, the more a strain showed signs of resistance to one peptide, the less resistant it often became to the other one.

That included P. falciparum strains that are resistant to currently used anti-malarial drugs of choice, artemisinin and its derivatives. In fact, the combination of one or another peptide with any of several drugs seemed to imbue each of them with new strength.

If I were P. falciparum, I'd be very afraid.

Photo by Arisa Chattasa

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