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 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.
This is an illustration of Anopheles darlingi.
Credit: UC San Diego School of Medicine
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 malaria parasite from oxidative stress in red blood cells, creating an environment in which the parasite survives," said senior author Lars Bode, PhD, assistant professor in the UCSD Department of Pediatrics, Division of Neonatology and the Division of Gastroenterology, Hepatology 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.
Contributors to the study include Janina Preuss, UC San Diego, Justus-Liebig-University and Sanford-Burnham Medical Research Institute; Esther Jortzik, Stefan Rahlfs and Katja Becker, Justus-Liebig-University; Patrick Maloney, Satyamaheshwar Peddibhotla, Paul Hershberger, Eliot Sugarman, Becky Hood, Eigo Suyama, Kevin Nguyen, Stefan Vasile, Arianna Mangravita-Novo, Michael Vicchiarelli, Danielle McAnally, Layton H. Smith. Gregory P. Roth, Michael P. Hedrick, Palak Gosalia, Monika Milewski, Yujie Linda Li, Eduard Sergienko, Jena Diwan, Thomas D.Y. Chung, and Anthony B. Pinkerton, Sanford-Burnham.
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 Medical Research Institute, one of the comprehensive centers of the NIH Molecular Libraries Probe Production Centers Network (MLPCN).
Debra Kain | EurekAlert!
Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel
Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
26.04.2017 | Materials Sciences
26.04.2017 | Agricultural and Forestry Science
26.04.2017 | Physics and Astronomy