Innovative Malaria Prodrug Targets Liver, Enhances Efficacy While Reducing Toxicity, Preclinical Studies Show
By Dr. Liji Thomas, MD
Reviewed by Lily Ramsey, LLM
Malaria remains a significant threat, with nearly 250 million infections and over 600,000 deaths in 2021 alone. The parasite’s complex lifecycle poses challenges in treating the disease. Tafenoquine, an 8-aminoquinoline drug, has shown promise as a single-dose radical cure for malaria, but its use is limited in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common enzyme defect.
To address this challenge, researchers have developed a liver-targeted polymeric prodrug of tafenoquine, administered subcutaneously (SC). This modification aims to enhance the drug’s therapeutic index by reducing peak blood concentrations and minimizing hemolytic anemia risk.
The prodrug is designed to remain stable in the bloodstream and be broken down by enzymes within the liver, optimizing transport through liver cells. This approach targets the hypnozoite stage of the parasite, which is responsible for relapses and transmission.
In comparative studies, the prodrug demonstrated improved efficacy against Plasmodium berghei sporozoites and reduced hemolysis in a humanized mouse model of G6PD deficiency.
- Using a primate model, the researchers evaluated the prodrug’s effectiveness against Plasmodium cynomolgi hypnozoites.
- The prodrug exhibited increased stability, liver exposure, and selectivity, resulting in complete parasite elimination.
- Importantly, hemotoxicity was reduced more than twofold compared to oral tafenoquine in the G6PD deficiency model.
The researchers also optimized the prodrug’s design to reduce production costs by 36%, making it more accessible in low-resource settings.
“These results show how the polymer could be engineered and optimized for COGS requirements and health equity, rather than by the therapeutic index alone,” the researchers write.
The liver-targeted tafenoquine prodrug platform holds promise for radical malaria cure, particularly in individuals with G6PD deficiency. Further research is needed to validate these findings in human clinical trials.
This study demonstrates the potential of prodrug modifications to improve the safety and efficacy of existing antimalarial drugs, paving the way for more effective and equitable malaria treatment strategies.
Mehek 
Divya