East Montgomery Times

Antimalarial drug resistance poses a significant challenge in the fight against malaria, affecting over 250 million people annually and causing more than 600,000 deaths. Researchers from the Children’s Hospital of Philadelphia (CHOP) have discovered a novel approach that could aid in developing new antimalarial treatments. The study, published in the Proceedings of the National Academy of Sciences, explores how malarial parasites utilize a human blood cell enzyme to enhance drug effectiveness.

Current treatments, including artemisinin-based combination therapies (ACT), face resistance challenges, particularly in Southeast Asia and Africa. The research highlights prodrugs as a promising strategy for overcoming these issues. Prodrugs are initially inactive but become effective once activated by enzymes within the body. This approach offers targeted treatment capabilities akin to a "Trojan horse."

Audrey R. Odom-John, MD, PhD, chief of the Division of Infectious Diseases at CHOP, stated that understanding which enzymes can activate prodrugs is crucial for future strategies: “Prodrugging is an enticing strategy because these drugs have methods for getting through the layers of protection offered by membranes of the parasite and host cells.”

The study identifies acylpeptide hydrolase (APEH), a human enzyme found in red blood cells, as critical for activating antimalarial prodrugs known as lipophilic ester prodrugs. Once inside the parasite's cytoplasm, APEH activates these prodrugs significantly enhancing their potency.

The findings suggest this method could help design "resistance-proof" drugs since mutations in host enzymes like APEH are unlikely to occur within parasites. First study author Sesh A. Sundararaman commented on this potential: “Based on our findings, we believe that leveraging an internalized host enzyme would circumvent these issues and enable the design of prodrugs with higher barriers to drug resistance.”

The research received support from various grants and awards including those from PIDS-St. Jude Children’s Research Hospital Fellowship Award in Basic and Translational Science and several National Institutes of Health grants.

Sundararaman et al's work titled “Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase” is available online with DOI: 10.1101/2024.08.30.610542.