Breakthrough Discovery offers hope for a more effective malaria treatment

Breakthrough Discovery offers hope for a more effective malaria treatment

Antimalarial drug resistance is a pressing issue in combating the spread of malaria worldwide. In a new study, researchers at Children's Hospital of Philadelphia (Chop) discovered a key process by which malaria parasites engage a human blood cell enzyme that could provide a new approach to antimalarial treatment. The results published today in the journalProceedings of the National Academy of SciencesProvide new insights into designing medicines that more effectively treat patients affected by this devastating infectious disease.

Despite many medications and preventative strategies to treat or stop the spread of malaria, the life-threatening disease continues to infect more than 250 million people, resulting in more than 600,000 deaths, most of which occur in children under 5 years of age. When this challenge arises, the malaria parasites have become resistant to almost every antimalarial treatment available. While a class of drugs known as artemisinin-based combination therapies (ACT) have helped save millions of lives that would otherwise have been claimed by malaria, trade-resistant strains of malaria have been found in Southeast Asia and Africa. New treatment strategies are urgently needed to combat this disease.

Many potential drugs fail in development because they are poorly absorbed in the gastrointestinal tract or are absorbed and removed from the body too quickly. However, a promising strategy for drug development is the use of prodrugs, which are used to improve a drug's ability to be absorbed or reach its target. Prodrugs act like a Trojan horse in that they are able to offer a more targeted attack against infections and diseases once they break through and reach the relevant tissues or cells. However, prodrugs are inactive and typically must be activated by an enzyme to achieve their desired effect. Chop researchers wanted to understand how antimalarial progs are activated to identify a way to treat malaria more effectively.

Prodrugging is a tempting strategy because these drugs have methods of reaching the protective layers offered by membranes of the parasite and host cells, as well as a drug warhead that effectively kills the parasite. We have been working on prodrugs that could be effective for treating malaria, but we also need to learn what types of enzymes within the parasite can activate the prodrug, as this information is critical to understanding the nature of the target for future antimalarial strategies. “

Audrey R. Odom-John, MD, PhD, senior study author, chief of infectious diseases at Chop

In this study, researchers found that a human enzyme acylpeptide hydrolase (Apeh) is the key activating enzyme of several antimalarial prodrugs known as lipophilic ester prodrugs. The Apeh enzyme is normally found in red blood cells. However, in the case of malaria, the enzyme is absorbed into the parasite's cytoplasm, where Apeh retains its activity. The researchers' results suggest that Apeh activates antimalarial progs within the parasite and significantly increases the effectiveness of the lipophilic ester products.

While this finding was unexpected, the researchers note that it could help design “resistance-tight” prosgs. Mutations in prodrug-activating enzymes are a common mechanism for resistance to antimicrobial drugs. However, the parasite would not be able to mutate a host enzyme, reducing the likelihood that drug resistance could develop through this mechanism.

“Based on our findings, we believe that using an internalized host enzyme would circumvent these problems and enable the design of prodrugs with higher barriers to drug resistance,” said first study author Sesh A. Sundararaman, MD, a senior physician in the Division of Infectious Diseases at Chops. “This could eventually lead to the development of parasite- or bacteria-specific prodrugs that are less dependent on specific enzymes.”

This study was supported by the PIDS-ST. Jude Children's Research Hospital Fellowship Award in Basic and Translational Science, The National Institutes of Health Grants R01AI171514, R01AI123433, T32AI141393, The Doris Duke Foundation Paragon of Research Excellence Award, The Indiana Academy of Sciences Senior Research Grant, and Chop.

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