The title of the post is a copy and paste from the subtitle and fourth, fifth and sixth paragraphs of the linked academic press release here:
Researchers tested chemical compounds for their ability to inhibit the malaria parasite at an earlier lifecycle stage than most current drugs, revealing chemical starting points for new malaria preventatives
The team spent two years extracting malaria parasites from hundreds of thousands of mosquitoes and using robotic technology to systematically test more than 500,000 chemical compounds for their ability to shut down the malaria parasite at the liver stage. After further testing, they narrowed the list to 631 promising compounds that could form the basis for new malaria prevention drugs.
To help speed this effort, the researchers made the findings open source, meaning the data are freely shared with the scientific community.
“It’s our hope that, since we’re not patenting these compounds, many other researchers around the world will take this information and use it in their own labs and countries to drive antimalarial drug development forward,” Winzeler said.
Yevgeniya Antonova-Koch, Stephan Meister, Matthew Abraham, Madeline R. Luth, Sabine Ottilie, Amanda K. Lukens, Tomoyo Sakata-Kato, Manu Vanaerschot, Edward Owen, Juan Carlos Jado Rodriguez, Steven P. Maher, Jaeson Calla, David Plouffe, Yang Zhong, Kaisheng Chen, Victor Chaumeau, Amy J. Conway, Case W. McNamara, Maureen Ibanez, Kerstin Gagaring, Fernando Neria Serrano, Korina Eribez, Cullin McLean Taggard, Andrea L. Cheung, Christie Lincoln, Biniam Ambachew, Melanie Rouillier, Dionicio Siegel, François Nosten, Dennis E. Kyle, Francisco-Javier Gamo, Yingyao Zhou, Manuel Llinás, David A. Fidock, Dyann F. Wirth, Jeremy Burrows, Brice Campo, Elizabeth A. Winzeler.
Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.
Science, 2018; 362 (6419): eaat9446
A path to tackle liver-stage parasites
Malaria parasites are evolutionarily prepared to resist drug attack. Resistance is emerging to even the latest frontline combination therapies, which target the blood stages of the Plasmodium parasite. As an alternative strategy, Antonova-Koch et al. investigated the possibilities of drugs against liver-stage parasites (see the Perspective by Phillips and Goldberg). To do so, they devised a luciferase-reporter drug screen for the rodent parasite Plasmodium berghei. Three rounds of increasingly stringent screening were used. From this regime, several chemotypes that inhibit Plasmodium mitochondrial electron transport were identified. Excitingly, several new scaffolds, with as-yet-unknown modes of action but solely targeting the parasites’ liver stages, emerged as promising drug leads for further development.
Science, this issue p. eaat9446; see also p. 1112
INTRODUCTION Malaria remains a devastating disease, affecting 216 million people annually, with 445,000 deaths occurring primarily in children under 5 years old. Malaria treatment relies primarily on drugs that target the disease-causing asexual blood stages (ABS) of Plasmodium parasites, the organisms responsible for human malaria. Whereas travelers may rely on short-term daily chemoprotective drugs, those living in endemic regions require long-term malaria protection such as insecticide-treated nets (ITNs) and vector control. However, ITNs do not fully shield individuals from malaria, may lose potency with time, and can be bulky and difficult to use. Another concern is that mosquitos may become resistant to the active insecticides that are used in ITNs and vector control.
RATIONALE As the possibility of malaria elimination becomes more tangible, the ideal antimalarial medicine profile should include chemoprotection. Chemoprotective medicines typically work against the exoerythrocytic parasite forms that invade and develop in the liver and are responsible for the earliest asymptomatic stage of the infection. Such medicines could be formulated to provide long-acting prophylaxis, safeguarding individuals that are living near or traveling to areas that have been cleared of parasites. Long-acting chemoprotection in endemic regions could also greatly reduce circulating parasite numbers and potentially replace a vaccine in an elimination campaign. Although millions of compounds have been screened for activity against parasite ABS, and some have been subsequently tested for potential prophylactic activity, large-scale searches that begin with prophylactic activity have not been performed because of the complexity of the assay: This assay requires the production of infected laboratory-reared mosquitoes and hand-dissection of the sporozoite-infected salivary glands from mosquito thoraxes.
RESULTS To discover leads for next-generation chemoprotective antimalarial drugs, we used luciferase-expressing Plasmodium spp. parasites, dissected from more than a million mosquitoes over a 2-year period, to test more than 500,000 compounds for their ability to inhibit liver-stage development of malaria (681 compounds showed a half-maximal inhibitory concentration of <1 μM). Cluster analysis identified potent and previously unreported scaffold families, as well as other series previously associated with chemoprophylaxis. These leads were further tested through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity. This work revealed compound classes that are likely to provide symptomatic relief from blood-stage parasitemia in addition to providing protection. Target identification by use of functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unknown mechanisms of action, some which may disrupt the host pathogen signaling.
CONCLUSION Our data substantially expands the set of compounds with demonstrated activity against two known targets of chemoprotective drugs, cytochrome bc1 and dihydroorotate dehydrogenase. These present a rich collection of chemical diversity that may be exploited by members of the community seeking to accelerate malaria elimination with chemoprotection and chemoprophylaxis through open-source drug discovery.
To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.