A 'Trojan Horse' approach to develop new antimalarial drugs

Antimalarial drug resistance is a pressing issue in combating the spread of malaria worldwide. In a new study, researchers from Children’s Hospital of Philadelphia (CHOP) discovered a key process where malarial parasites take up a human blood cell enzyme, which could provide a new approach for antimalarial treatment. The findings, published in the journal Proceedings of the National Academy of Sciences, provide new insights into how to design drugs that more effectively treat patients affected by this devastating infectious disease.

Despite many drugs and preventive strategies used to treat or halt the spread of malaria, the life-threatening disease continues to infect more than 250 million people each year, resulting in more than 600,000 deaths, the majority of which occur in children under the age of 5.

Compounding this challenge, malarial parasites have become resistant to nearly every available antimalarial treatment. While a class of drugs known as artemisinin-based combination therapies (ACT) has helped save millions of lives that would have otherwise been claimed by malaria, ACT-resistant strains of malaria have been found in Southeast Asia and Africa. New treatment strategies are urgently needed to combat this disease.

Antimalarial prodrugs

Many potential drugs fail in development because they are poorly absorbed in the gastrointestinal tract or absorbed and removed from the body too rapidly. However, one 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 work 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 appropriate tissues or cells. However, prodrugs are inactive and must be activated, typically by an enzyme, to achieve their desired effect. Researchers at CHOP set out to understand how antimalarial prodrugs are activated, in the hopes of identifying a way to more effectively treat malaria.

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“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, as well as a drug ‘warhead’ that effectively kills the parasite,” said senior study author Audrey R. Odom-John, MD, PhD, chief of the Division of Infectious Diseases at CHOP.

“We’ve been working on prodrugs that might be effective for treating malaria, but in doing so, we’ve also needed to learn what kinds of enzymes within the parasite are capable of activating the prodrug, as that information is critical to understanding the nature of the target for future antimalarial strategies,” Odom-Jon said.

Lowering drug resistance of prodrugs

In this study, researchers found that a human enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple 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 taken into the parasite’s cytoplasm where APEH retains its activity. The researchers’ findings suggest that APEH activates antimalarial prodrugs within the parasite, greatly increasing the potency of the lipophilic ester prodrugs.

While this finding was unexpected, the researchers note that it could help design “resistance-proof” prodrugs. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance. However, the parasite would be unable to mutate a host enzyme, decreasing the likelihood that drug resistance could develop by this mechanism.

“Based on our findings, we believe that leveraging an internalized host enzyme would circumvent these issues and enabling the design of prodrugs with higher barriers to drug resistance,” said first study author Sesh A. Sundararaman, MD, PhD, an attending physician with the Division of Infectious Diseases at CHOP. “This might eventually lead to the development of parasite- or bacteria-specific prodrugs that are less reliant on specific enzymes.”