Hitting Malaria In The Proteasome

There is an urgent need for new antimalarial drugs because the malaria parasite has developed resistance to the most widely used therapies—combinations of artemisinin and other drugs—and most treatments don’t prevent transmission, which allows resistance to spread.

Researchers now report a small molecule that can kill the parasite in mice with few side effects (Nature 2016, DOI: 10.1038/nature16936). The molecule works by inhibiting the proteasome, the cell’s protein-degrading machine, in the parasites but to a much lesser extent in the host. Such selective proteasome inhibitors could complement current antimalarial drugs and lead to medications for other infectious diseases.

The malaria parasite has a complex life cycle, in which it morphs through nine forms in mosquitoes and people. Researchers have been actively investigating proteasome inhibitors as antimalarial agents because inhibiting the proteasome can kill all stages of the parasite, reducing the possibility that one or more will survive treatment. Also, recent findings suggest proteasome inhibitors suppress artemisinin-resistant strains. But the inhibitors developed to date hit both the malarial and human proteasomes to a similar extent, making them toxic to people.

In the new study, Matthew Bogyo and coworkers at Stanford University School of Medicine first screened a library of peptides to determine sequences favored for degradation by parasite proteasomes but not human ones. They used that information to design selective inhibitors.

Then the Stanford team and Paula C. A. da Fonseca of the MRC Laboratory of Molecular Biology used cryoelectron microscopy to obtain a structure of the parasite proteasome bound to a designed inhibitor. This structure of the malarial proteasome at the inhibitor-binding site provided a guide for further optimization of the inhibitor structures.

The researchers’ most successful parasite-selective inhibitor, a peptidelike molecule called WLL-vs, killed artemisinin-sensitive and -resistant malaria parasites. A single dose of WLL-vs substantially reduced parasite levels in mice without any apparent toxic effects.

Malaria treatment specialist Benjamin Mordmüller of the University of Tübingen says the development is promising because previous studies have shown that proteasome inhibitors have the potential to kill all the different stages of the malaria life cycle. No current antimalaria drugs hit all stages, and existing drugs that do hit more than one stage aren’t equally effective against the different ones.

Parasite proteasome expert Karine G. Le Roch comments that a selective proteasome inhibitor such as WLL-vs could be combined with artemisinin to decrease the spread of malarial drug resistance, if it can pass efficacy and toxicity trials.

Puran S. Sijwali of the Centre for Cellular & Molecular Biology, in Hyderabad, India, a parasite drug-target specialist, notes that the general design strategy could also lead to proteasome-specific drug leads for other infectious diseases, such as trypanosome and amoeba infections, leishmaniasis, and toxoplasmosis.

This article has been translated into Spanish by Divulgame.org and can be found here.