Potential New Drug Blocks Critical Malaria Parasite Enzyme

The identification of a low molecular weight inhibitor of the form of the enzyme glucose-6-phosphate dehydrogenase (G6PD) found in the malaria parasite Plasmodium falciparum may pave the way for a new generation of anti-malarial drugs.

G6PD is a cytosolic enzyme with a role in the pentose phosphate pathway, a metabolic pathway that supplies reducing energy to cells (such as erythrocytes) by maintaining the level of the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH). NADPH in turn maintains the level of glutathione in these cells, which helps protect red blood cells against oxidative damage. G6PD is essential for proliferating and propagating P. falciparum, and the parasite form of the enzyme differs structurally and mechanistically from the human.

Investigators at the University of California, San Diego (USA) and their colleagues at the Sanford-Burnham Medical Research Institute (La Jolla, CA, USA) and Justus-Liebig-University (Giessen, Germany) used advanced high-throughput screening techniques to search the more than 340,000 compounds in the [US] National Institutes of Health's (Bethesda, MD, USA) Molecular Libraries Small Molecule Repository (MLSMR) for inhibitors of the form of G6PD found in P. falciparum (PfG6PD).

Results published in the July 19, 2012, online edition of the Journal of Medicinal Chemistry revealed that a compound labeled ML276 was highly effective against P. falciparum in culture, and had good drug-like properties, including high solubility and moderate microsomal stability. At the same time, ML276 did not demonstrate any inhibitory effects towards the human form of GP6D.

“The enzyme G6PD catalyzes an initial step in a process that protects the malaria parasite from oxidative stress in red blood cells, creating an environment in which the parasite survives,” said senior author Dr. Lars Bode, assistant professor of pediatrics at the University of California, San Diego. “People with a natural deficiency in this enzyme are protected from malaria and its deadly symptoms. ML276 is a very promising basis for future drug design of new antimalarial therapeutics, as we did not want to interfere with the human form of the enzyme and risk potential side effects.”

Related Links:
University of California, San Diego
Sanford-Burnham Medical Research Institute
Justus-Liebig-University