How a Prodrug Approach May Aid In Antimalarial Development
Sesh Sundararaman, MD, PhD, discusses his findings and how this approach can be triggered to minimize undesirable treatment features and open the door to newer treatment possibilities.
Antimalarial treatments continue to face resistance in both Asia and Africa—2 continents devastated by this vector-borne disease. Sesh Sundararaman, MD, PhD, an attending physician with the Division of Infectious Diseases at the Children’s Hospital of Philadelphia (CHOP), points out that not only is resistance growing with existing artemisinin-based combination therapies (ACTs), but a particular strain can be much more severe.
“We know that it's occurring in a few countries in Africa. It's a big risk because the majority of cases of falciparum malaria, which is the deadliest form of malaria, occur in Sub-Saharan Africa,” Sundararaman said. “So if we lose our ability to treat patients with those drugs, we will see an increase in mortality and morbidity.”
Developing new therapies can be challenging because they are either poorly absorbed in the gastrointestinal tract or absorbed and eliminated from the body too rapidly. One potential strategy for drug development is the use of prodrugs, which are designed to improve a drug’s ability to be absorbed or to reach its target. Prodrugs work like a Trojan horse, offering a more targeted attack against infections and diseases once they reach the appropriate tissues or cells. However, prodrugs are inactive and must be activated, typically by an enzyme, to achieve their desired effect.1
Sundararaman and colleagues at CHOP studied how antimalarial prodrugs are activated, with the goal of identifying a way to more effectively treat malaria.
“Prodrugging is really a way to help our drugs get to where they need to go,” Sundararaman said. “And prodrugs are actually used very commonly in the pharmaceutical industry. The main reason is that we have drugs that may have properties making them poorly absorbed. One of the things chemists can do is attach these prodrug groups that mask those properties, making a poorly absorbed drug better absorbed.”
Sundararaman and his team found that a human enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme for 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.1
“It seems that at least 2 different pivaloxymethyl (POM) prodrugs—the 'POM' group being the focus of this paper—are activated by the enzyme, which suggests that other prodrugs could also be activated by the same human enzyme that is taken up by the parasite,” Sundararaman said.
Their findings were recently published in the journal Proceedings of the National Academy of Sciences.
