Novel anti-malarial drug target identified

July 19, 2012, University of California - San Diego
This is an illustration of Anopheles darlingi. Credit: UC San Diego School of Medicine

An international team of scientists, led by researchers from the Department of Pediatrics at the University of California, San Diego School of Medicine, have identified the first reported inhibitors of a key enzyme involved in survival of the parasite responsible for malaria. Their findings, which may provide the basis for anti-malarial drug development, are currently published in the online version of the Journal of Medicinal Chemistry.

Tropical malaria is responsible for more than 1.2 million deaths annually. Severe forms of the disease are mainly caused by the parasite Plasmodium falciparum, transmitted to humans by female . has not been possible due to the lack of vaccines and the parasite's ability to develop resistance to most drugs.

The researchers conducted high-throughput screening of nearly 350,000 compounds in the National Institutes of Health's Molecular Libraries Small Molecule Repository (MLSMR) to identify compounds that inhibit an enzyme which plays an important role in parasite development: Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD) is essential for proliferating and propagating P. falciparum.

"The enzyme G6PD catalyzes an initial step in a process that protects the from oxidative stress in , creating an environment in which the parasite survives," said senior author Lars Bode, PhD, assistant professor in the UCSD Department of Pediatrics, Division of and the Division of Gastroenterology, and Nutrition. People with a natural deficiency in this enzyme are protected from malaria and its deadly symptoms, an observation that triggered the reported research.

The parasitic form of the enzyme (PfG6PD) is what contributes the majority of G6PD activity in infected red blood cells. Because the parasite lives in the blood of a malaria-infected person, the scientists aimed at identifying compounds that inhibit the parasitic form but not the human form of the enzyme. "We didn't want to interfere with the human form of the enzyme and risk potential side effects," Bode explained.

Scientific testing had previously been limited by a lack of recombinant PfG6PD. Team members in the lab of Katja Becker, PhD, at the Interdisciplinary Research Center at Justus-Liebig-University in Giessen, Germany produced the first complete and functional recombinant PfG6PD, and researchers led by Anthony Pinkerton, PhD, at Sanford-Burnham Medical Research Institute used it to identify the lead compound resulting from their efforts, ML276.

ML276 represents the first reported selective PfG6PD inhibitor, which stops the growth of malaria parasites in cultured red blood cells – even those parasites that developed resistance to currently available drugs. "ML276 is a very promising basis for future drug design of new anti-malarial therapeutics," said Bode.

Related Stories

Recommended for you

Researchers hope to be able to replace dysfunctional brain cells

November 20, 2018
A new study by researchers at Karolinska Institutet supports the theory that replacement of dysfunctional immune cells in the brain has therapeutic potential for neurodegenerative diseases like ALS and Alzheimer's disease. ...

RNAi therapy mitigates preeclampsia symptoms

November 19, 2018
A collaboration of scientists from the University of Massachusetts Medical School, Beth Israel Deaconess Medical Center and Western Sydney University, have shown that an innovative new type of therapy using small interfering ...

Skeletal imitation reveals how bones grow atom-by-atom

November 19, 2018
Researchers from Chalmers University of Technology, Sweden, have discovered how our bones grow at an atomic level, showing how an unstructured mass orders itself into a perfectly arranged bone structure. The discovery offers ...

Signal peptides' novel role in glutamate receptor trafficking and neural synaptic activity

November 19, 2018
Glutamate is the major excitatory neurotransmitter in the brain, and the postsynaptic expression level of glutamate receptors is a critical factor in determining the efficiency of information transmission and the activity ...

New insights into how an ordinary stem cell becomes a powerful immune agent

November 19, 2018
How do individual developing cells choose and commit to their "identity"—to become, for example, an immune cell, or a muscle cell, or a neuron?

A molecule for fighting muscular paralysis

November 19, 2018
Myotubular myopathy is a severe genetic disease that leads to muscle paralysis from birth and results in death before two years of age. Although no treatment currently exists, researchers from the University of Geneva (UNIGE), ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.