An international team of scientists, including researchers at the University of California, San Diego (UCSD) and Sanford-Burnham Medical Research Institute, 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, were published July 19 in the Journal of Medicinal Chemistry.
According to the World Health Organization, there were 216 million cases of malaria worldwide in 2010. Severe forms of the disease are mainly caused by the parasite Plasmodium falciparum, transmitted to humans by female Anopheles mosquitoes. Malaria eradication 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 to identify compounds that inhibit an enzyme that plays an important role in parasite development: Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD). PfG6PD is essential for proliferating and propagating P. falciparum.
“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 Lars Bode, Ph.D., assistant professor in the Department of Pediatrics at UCSD, referring to a chemical reaction that can damage cellular components. People with a natural deficiency in G6PD 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, Ph.D., at Justus-Liebig-University in Germany, produced the first complete and functional recombinant PfG6PD. Researchers led by Anthony Pinkerton, Ph.D. at Sanford-Burnham 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.
The study was supported by the National Institutes of Health (1R21AI082434), the Deutsche Forschungsgemeinschaft, and an NIH Molecular Libraries grant (U54 HG005033) to the Conrad Prebys Center for Chemical Genomics at Sanford-Burnham, one of the comprehensive centers of the NIH Molecular Libraries Probe Production Centers Network (MLPCN).
Click here to read the press release on UCSD’s site.
Janina Preuss, Patrick Maloney, Satyamaheshwar Peddibhotla, Michael P. Hedrick, Paul Hershberger, Palak Gosalia, Monika Milewski, Yujie Linda Li, Eliot Sugarman, Becky Hood, Eigo Suyama, Kevin Nguyen, Stefan Vasile, Eduard Sergienko, Arianna Mangravita-Novo, Michael Vicchiarelli, Danielle McAnally, Layton H. Smith, Gregory P. Roth, Jena Diwan, Thomas D.Y. Chung, Esther Jortzik, Stefan Rahlfs, Katja Becker, Anthony B. Pinkerton, & Lars Bode (2012). Discovery of a Plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase inhibitor (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (ML276) that reduces paras Journal of Medicinal Chemistry : 10.1021/jm300833h