How a cancer drug could be repurposed to fight the parasites that cause malaria

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Colorized electron micrograph showing the malaria parasite (right, blue) attaching to a human red blood cell. Inset shows attachment point detail at higher magnification. Credit: NIAID

Malaria is caused by the parasite Plasmodium falciparum, which is transmitted by mosquitoes. The World Health Organization (WHO) estimates that in 2020 there were 241 million cases and 627,000 deaths worldwide, 94% of cases and 96% of deaths occur in sub-Saharan Africa. Tragically, malaria claims the life of a child under five every minute.

As mosquito habitats have expanded with global warming, people are more susceptible to contracting the malaria parasite. WHO advises vector control to reduce the number of mosquitoes and thus decrease the likelihood of mosquito bites, as well as chemoprevention to prevent disease in the absence of an effective vaccine.

The parasite Toxoplasma gondii, a close cousin of Plasmodium, infects 2 billion people worldwide and is the cause of the foodborne illness toxoplasmosis. Babies and people with weakened immune systems, such as those with AIDS or cancer, are more vulnerable to disease. Studies also suggest that Toxoplasma parasites have long-lasting effects on a person’s personality and behavior due to their ability to nestle in the human brain, and they may play a role in schizophrenia and bipolar disorder. .

Despite scientists’ tireless efforts to eradicate these two parasite-borne diseases, currently available drugs to treat them are suboptimal and few, if any, alternatives exist.

Undesirable side effects

Treatment for toxoplasmosis often has serious side effects such as liver toxicity and suppression of bone marrow, which is involved in blood cell production, putting immunocompromised people at even greater risk. Also, no drug can kill Toxoplasma when the parasite establishes itself as a latent infection in the muscles and brain. Even where drugs exist, cost can be a factor – one option, Daraprim, made news in 2015 after Turing Pharmaceuticals raised the price from $13.50 to $750 per pill in the United States, threatening the access for vulnerable patients.

In areas where malaria is endemic, artemisinin-based combination therapy (ACT) is now the first-line treatment. Artemisinin is a plant extract derived from traditional Chinese herbal medicine and first synthesized by Dr. Tu Youyou, who was awarded the 2015 Nobel Prize. However, a major concern is the spread of resistance to both artemisinin and alternative drug combinations, initially in Southeast Asia and recently in Rwanda and Uganda. Resistance occurs when a drug loses its effectiveness and can no longer completely cure the infection it was meant to treat.

A drug development strategy that can save a lot of time and money in “repurposing” originally approved treatments for other diseases or conditions. A well-known example is sildenafil, originally developed to treat chest pain caused by coronary heart disease. Although it failed clinical trials, scientists found that one of the drug’s side effects was erection, and it was designed like Viagra, which treats erectile dysfunction. As researchers rushed to develop COVID-19 therapies, drug reuse received a lot of attention.






Fighting parasites with a new drug

Our team has just achieved a scientific breakthrough with the discovery of a new anti-parasite drug, altiratinib. Originally developed to treat glioblastoma, an aggressive brain cancer, we determined that altiratinib has potent parasiticidal activity against Toxoplasma. Altiratinib is also active against Eimeria and Neospora, two parasites of veterinary importance that cause significant economic losses in livestock.

When talking about drugs, scientists often use the term “mechanism of action” (MOA) to describe what the drug actually does in the body. To better understand how altiratinib works in the parasite, identifying its “target” is the holy grail. Using state-of-the-art genetics, we determined that the primary target of altiratinib was a kinase, an enzyme that chemically modifies other molecules and in doing so regulates their biological activity. In Toxoplasma the kinase is known as PRP4K, while in Plasmodium it is called CLK3.

Most cellular functions are carried out by proteins, which are large, complex molecules. The information that allows cells to make proteins is contained in DNA. The production of a given protein begins with the transcription (i.e. the “copy”) of the corresponding gene into an immature molecule of messenger RNA (mRNA).

Immature mRNA is a “work in progress”, similar to a sketch that needs polishing. Secondly, the mRNA will undergo a process called “splicing”. The enzymes will remove unnecessary parts of the immature mRNA molecule, like tailors alter a garment. The resulting “matured” mRNA can be considered the “final sketch” that will be used for protein production. If something goes wrong during splicing, the resulting protein may not work as expected or may not work at all.

The PRP4K kinase is one of the “tailors” involved in this splicing step. Its inhibition by altiratinib disrupts genome-wide parasite splicing, leading to chaos in protein production and parasite death.

Identification of regions of interest

Certain regions of proteins interact with molecules in their environment and are therefore essential for their functioning. Using state-of-the-art methods, we were able to determine the region of PRP4K where the chemical reactions occur and to which altiratinib binds. If the binding site is better defined, more effective compounds can be made.

We also learned more about the multi-species antimalarial drug TCMDC-135051, which is not yet commercially available. It can also bind to PRPK4, and since TCMDC-135051 and altiratinib have such different chemical spaces and probably work in different ways, therapies could be developed based on a combination of the two, which could theoretically limit the emergence of resistance.

Our discovery highlights the importance of the PRP4K/CLK3 kinase as a drug target in parasites and makes altiratinib, originally developed for the treatment of cancer, a therapeutic option not only for the treatment of malaria, but also toxoplasmosis and parasitic animal diseases.


Finding new drugs to fight malaria


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