Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.

Stephan Meister, David M Plouffe, Kelli L Kuhen, Ghislain M C Bonamy, Tao Wu, S Whitney Barnes, Selina E Bopp, Rachel Borboa, A Taylor Bright, Jianwei Che, Steve Cohen, Neekesh V Dharia, Kerstin Gagaring, Montip Gettayacamin, Perry Gordon, Todd Groessl, Nobutaka Kato, Marcus C S Lee, Case W McNamara, David A Fidock, Advait Nagle, Tae-gyu Nam, Wendy Richmond, Jason Roland, Matthias Rottmann, Bin Zhou, Patrick Froissard, Richard J Glynne, Dominique Mazier, Jetsumon Sattabongkot, Peter G Schultz, Tove Tuntland, John R Walker, Yingyao Zhou, Arnab Chatterjee, Thierry T Diagana, Elizabeth A Winzeler

Index: Science 334 , 1372-7, (2011)

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Abstract

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.