Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery

• DOI: 10.1126/science.1211936
• Publication Date: 2011-11-18T05:55:54Z
• Authors: Stephan Meister; David M. Plouffe; Kelli L. Kuhen; Ghislain M. C. Bo...; 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 Sattabon...; Peter G. Schultz; Tove Tuntland; John R. Walker; Yingyao Zhou; Arnab Chatterjee; Thierry T. Diagana; Elizabeth A. Winz...
• Keywords: Plasmodium (life cycle); Drug Development

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 set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) identified chemical scaffolds potent forms. From this screen, we an imidazolopiperazine scaffold series that was highly enriched among Plasmodium liver stages. The orally bioavailable lead confers complete causal prophylactic protection (15 milligrams/kilogram) rodent models shows vivo therapeutic activity. open-source tools resulting from our effort provide starting points for future discovery programs, as well opportunities researchers investigate the biology