As parasites become increasingly resistant to existing drugs, researchers at the University of California, Riverside are working to develop a new generation of treatments for two serious infectious diseases: malaria and babesiosis.
The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, has awarded two collaborative grants totaling more than $8 million to researchers at UC Riverside, UC Irvine, and Yale University to advance two promising classes of antiparasitic compounds toward preclinical development. UC Riverside will receive more than $2.5 million through the awards.
The projects target malaria, which continues to kill hundreds of thousands of people worldwide each year, and babesiosis, a tick-borne disease that is becoming more common in the United States as tick populations expand. Both diseases are caused by closely related parasites that invade red blood cells, making it possible to develop treatments that work against both.
“The major issue is that the parasites are becoming resistant to current treatments,” said Karine Le Roch, professor of molecular, cell and systems biology at UC Riverside and a co-principal investigator on both grants. “We definitely need the next line of defense against these infectious diseases.”
The research builds on years of collaboration among Le Roch, UC Irvine chemist Christopher Vanderwal, and Yale University scientist Choukri Ben Mamoun. The three co-principal investigators and their teams combine expertise in medicinal chemistry, genetics, parasite biology, systems biology, and animal models to transform naturally occurring compounds into potential medicines.
“We already have promising lead compounds that are highly active against both Plasmodium and Babesia,” said Le Roch, the director of UCR’s Center for Infectious Disease and Vector Research. “Now the goal is to move those lead compounds toward preclinical development.”
One project focuses on leelamine-derived isonitriles (LDIs), compounds synthesized from leelamine, a natural product found in pine bark. The second investigates pyrroloiminoquinones (PIQs), a family of compounds originally isolated from marine sponges. Although the compounds come from different natural sources, both have shown potent activity against malaria and babesiosis parasites, including drug-resistant strains.
Le Roch explained that natural products have provided the foundation for many important medicines, but their chemical complexity often makes them difficult and expensive to manufacture.
“These compounds are usually extremely effective, but they are also very complex molecules,” Le Roch said. “These two projects focus on compounds that are easier and much less expensive to synthesize.”
Over the next five years, the researchers will optimize LDIs and PIQs, evaluate their safety, test them in laboratory and animal models, and identify exactly how they attack the parasites. Understanding their mechanisms of action will help the team refine the compounds and determine whether they target biological pathways that differ from those affected by today’s treatments.
“We hope to demonstrate that they target completely different pathways than the treatments currently being used,” Le Roch said. “That’s likely because both classes of compounds are active against drug-resistant parasite strains.”
The researchers also hope the compounds can interrupt transmission of the parasites, not simply eliminate infection.
“We’re aiming not only to kill the parasite but also to stop transmission,” Le Roch said. “Ultimately, the goal would be to develop an oral treatment.”
Le Roch’s laboratory will use systems biology approaches to determine how the compounds affect parasites at the molecular level and to identify how resistance could develop. Vanderwal’s group will synthesize and optimize the compounds, while Ben Mamoun’s laboratory will evaluate their effectiveness in animal models and lead studies on babesiosis.
“Today, biology is becoming so complicated that you need different types of expertise to move projects like this forward,” Le Roch said. “We need the chemist to create the compounds, experts to evaluate them in animal models, and our lab to understand how they work against the parasites.”
Because malaria and babesiosis belong to the same group of parasites, the findings could have implications beyond these two diseases. Le Roch said the compounds may eventually prove useful against other apicomplexan parasites, including Toxoplasma.
The grants will support undergraduate and graduate researchers in Le Roch’s laboratory.
“Funding projects like these is essential,” Le Roch said. “It allows us to train the next generation of scientists and develop treatments that could help people.”
The first award, “Therapeutic Potential and Mechanism of Action of Leelamine-Derived Isonitriles for Malaria and Babesiosis,” provides $4.07 million in total funding, including $1.18 million for UC Riverside. The second, “Optimization of the Pyrroloiminoquinone Scaffold for Malaria and Babesiosis Treatment,” provides $3.94 million, including $1.34 million for UC Riverside.
For Le Roch, the measure of success is straightforward.
“I really want these compounds to move to the next step in preclinical and clinical trials,” she said. “We definitely need new treatments against these devastating diseases.”
