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

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Science (New York, N.Y.), Volume: 334, Issue: 6061
December 9, 2011
Stephan Meister S, David M Plouffe DM, Kelli L Kuhen KL, Ghislain M C Bonamy GM, Tao Wu T, S Whitney Barnes SW, Selina E Bopp SE, Rachel Borboa R, A Taylor Bright AT, Jianwei Che J, Steve Cohen S, Neekesh V Dharia NV, Kerstin Gagaring K, Montip Gettayacamin M, Perry Gordon P, Todd Groessl T, Nobutaka Kato N, Marcus C S Lee MC, Case W McNamara CW, David A Fidock DA, Advait Nagle A, Tae-gyu Nam TG, Wendy Richmond W, Jason Roland J, Matthias Rottmann M, Bin Zhou B, Patrick Froissard P, Richard J Glynne RJ, Dominique Mazier D, Jetsumon Sattabongkot J, Peter G Schultz PG, Tove Tuntland T, John R Walker JR, Yingyao Zhou Y, Arnab Chatterjee A, Thierry T Diagana TT, Elizabeth A Winzeler EA

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.

Courtesy of the U.S. National Library of Medicine