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

Meister, S. and Plouffe, D. M. and Kuhen, K. L. and Bonamy, G. M. and Wu, T. and Barnes, S. W. and Bopp, S. E. and Borboa, R. and Bright, A. T. and Che, J. and Cohen, S. and Dharia, N. V. and Gagaring, K. and Gettayacamin, M. and Gordon, P. and Groessl, T. and Kato, N. and Lee, M. C. and McNamara, C. W. and Fidock, D. A. and Nagle, A. and Nam, T. G. and Richmond, W. and Roland, J. and Rottmann, M. and Zhou, B. and Froissard, P. and Glynne, R. J. and Mazier, D. and Sattabongkot, J. and Schultz, P. G. and Tuntland, T. and Walker, J. R. and Zhou, Y. and Chatterjee, A. and Diagana, T. T. and Winzeler, E. A.. (2011) Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science, Vol. 334, H. 6061. pp. 1372-1377.

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Official URL: http://edoc.unibas.ch/dok/A6002236

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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 <4,000 commercially available compounds with previously demonstrated blood stage activity (IC(50 )> 1 microM), 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. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) 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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for the Advancement of Science
ISSN:0036-8075
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Nov 2012 16:23
Deposited On:08 Nov 2012 16:16

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