Format

Send to

Choose Destination
Science. 2011 Dec 9;334(6061):1372-7. doi: 10.1126/science.1211936. Epub 2011 Nov 17.

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

Author information

1
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.

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.

PMID:
22096101
PMCID:
PMC3473092
DOI:
10.1126/science.1211936
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center