Drug researchers attack malaria parasite in multiple life stages

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Malaria, a mosquito-borne disease caused by the Plasmodium parasite, is a plague in the developing world, affecting 200 million people and killing nearly 450,000 people each year, many of whom are children five years and under. Although we have already implemented preventative drugs, they are simply not enough to combat the persistent parasite which is becoming increasingly resistant to drugs.

Paul Carlier, a professor in the chemistry department at Virginia Tech College of Science and director of the Virginia Tech Center for Drug Discovery, and his colleagues received a $ 3.7 million grant from the National Institutes of Health to begin further testing two of the effective antimalarial drug candidates that can kill Plasmodium parasites at three different stages of their development.

“The most effective malaria drug today is not safe for pregnant women or children five years of age or younger,” said Carlier, who is an affiliate faculty member at Virginia Tech’s Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, an arm of the Fralin Institute of Life Sciences. “These are the populations that are most in need of treatment, and yet they are the most vulnerable to drug toxicity. Because of this limitation and the parasite’s resistance to other existing drugs, we need to create better and better drugs. more secure. ”

In 2016, with support from a two-year grant from the National Institutes of Health, the team had a scaffold, or basic chemical structure, that they meticulously tweaked with various chemical modifications to see if it was any more. or less effective against malaria.

From the parent compound MMV008138, they have created two promising new antimalarial drug candidates, or compounds that have the potential to become a drug, called PRC1584 and PRC1590.

To understand malaria infection and how drugs can work against it, it is important to learn about the incredibly complex life cycle of malaria. Plasmodium parasite. The war of the parasite against the body takes place in three stages: the hepatic phase, the asexual blood phase, and the gametocyte or sexual blood phase.

But before the parasite can even attack the body, it first infects a female. Anopheles mosquito, the only mosquito species that can transmit malaria. When an unsuspecting mosquito feeds on a person infected with malaria, it sucks up a small amount of blood containing gametocytes which immediately turn into gametes, or parasitic eggs and sperm. After completing their entire life cycle within the insect, the adult parasites enter the mosquito’s saliva and are ready to be deployed.

After a human host is bitten by an infected mosquito, the parasites, which initially number less than 100, travel to the liver to multiply and form their infantry.

Then, like a hostile army invading the battlefield, thousands of Plasmodium the parasites enter the bloodstream and infect red blood cells (RBCs). Blood-stage parasites are the target of most antimalarial drugs because they induce the clinical signs of the disease, such as fever, vomiting and anemia. Symptoms appear when the amount of parasites in red blood cells reaches 100 million. The rapid development of parasites is linked to their asexual reproduction, which does not require eggs or sperm to reproduce.

In the bloodstream, parasites can also develop into a sexual form called the gametocyte stage. In this form, the parasites produce parasitic eggs and sperm so that they can be passed on to each other Anopheles mosquito vector.

“If you have this sexual form circulating in your blood and you get bitten by the mosquito, it’s the only stage in your life that can continue the cycle and infect mosquitoes,” Carlier said. “The ideal drug would break the cycle by targeting all three life stages: the liver stage for prevention, the asexual blood stage for treatment, and gametocytes to block disease transmission. “

The ultimate goal is to create an antimalarial that would have these characteristics, and also to cure severe malaria with a single oral dose.

To achieve these goals, Carlier will continue to collaborate with Maria Belen Cassera, associate professor of biochemistry and molecular biology and faculty member at the Center for Tropical & Emerging Global Diseases at the University of Georgia, and Max Totrov, computational chemist at Molsoft. , a leading provider of tools, databases and advisory services in the field of structural proteomics, bioinformatics and rational drug design.

After Carlier, a medical chemist, prepares new variants of the main antimalarial compounds, they will be sent to Cassera, who will test them for their antimalarial efficacy in a variety of cell and animal models. Max Totrov will bring his machine learning expertise to suggest other changes that would improve in vivo antimalarial efficacy and reduce toxicity to mammals.

The team is optimistic that their research will produce candidates for advanced preclinical assessment, a process that may require a partnership with a public-private partnership in global health. The road to drug development can be long, but it is often rewarded with fundamental breakthroughs in disease biology.

Virginia Tech recently filed for patents on both drug candidates, in addition to awarding the team a proof of concept award.

– This press release was originally published on the Virginia Tech website


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