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!
Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg
Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
19.10.2017 | Materials Sciences
19.10.2017 | Materials Sciences
19.10.2017 | Physics and Astronomy