Open-source discovery of chemical leads for next-generation chemoprotective antimalarials

07 Dec 2018

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


DOI: 10.1126/science.aat9446

Photo: gerasimov_foto_174/



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.


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.


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.


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.

Read the full article on Science's website.