Dataset Information

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

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.

SUBMITTER: Meister S

PROVIDER: S-EPMC3473092 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

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

Science (New York, N.Y.) 20111117 6061

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 sc ...[more]

PMID: 22096101

Similar Datasets

Project description:Most of current strategies for antiviral therapeutics target the virus specifically and directly, but an alternative approach to drug discovery might be to enhance the immune response to a broad range of viruses. Based on clinical observation in humans and successful genetic strategies in experimental models, we reasoned that an improved interferon (IFN) signaling system might better protect against viral infection. Here we aimed to identify small molecular weight compounds that might mimic this beneficial effect and improve antiviral defense. Accordingly, we developed a cell-based high-throughput screening (HTS) assay to identify small molecules that enhance the IFN signaling pathway components. The assay is based on a phenotypic screen for increased IFN-stimulated response element (ISRE) activity in a fully automated and robust format (Z'>0.7). Application of this assay system to a library of 2240 compounds (including 2160 already approved or approvable drugs) led to the identification of 64 compounds with significant ISRE activity. From these, we chose the anthracycline antibiotic, idarubicin, for further validation and mechanism based on activity in the sub-µM range. We found that idarubicin action to increase ISRE activity was manifest by other members of this drug class and was independent of cytotoxic or topoisomerase inhibitory effects as well as endogenous IFN signaling or production. We also observed that this compound conferred a consequent increase in IFN-stimulated gene (ISG) expression and a significant antiviral effect using a similar dose-range in a cell-culture system inoculated with encephalomyocarditis virus (EMCV). The antiviral effect was also found at compound concentrations below the ones observed for cytotoxicity. Taken together, our results provide proof of concept for using activators of components of the IFN signaling pathway to improve IFN efficacy and antiviral immune defense as well as a validated HTS approach to identify small molecules that might achieve this therapeutic benefit.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets