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Cell Host Microbe. 2016 Jan 13;19(1):114-26. doi: 10.1016/j.chom.2015.12.001. Epub 2015 Dec 31.

High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission.

Author information

1
The Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
2
Division of Pharmacology and Drug Discovery, Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
3
Division of Infectious Disease, Department of Medicine, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
4
Broad Institute, 415 Main Street, Cambridge MA 02142.
5
Medicines for Malaria Venture (MMV), PO Box 1826, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland.
6
Broad Institute, 415 Main Street, Cambridge MA 02142; Department of Chemistry and Chemical Biology, Harvard University, 7 Cambridge Center, Cambridge, MA 02142, USA.
7
Division of Pharmacology and Drug Discovery, Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: ewinzeler@ucsd.edu.

Abstract

Preventing transmission is an important element of malaria control. However, most of the current available methods to assay for malaria transmission blocking are relatively low throughput and cannot be applied to large chemical libraries. We have developed a high-throughput and cost-effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small molecules with transmission-blocking capacity. SaLSSA analysis of 13,983 unique compounds uncovered that >90% of well-characterized antimalarials, including endoperoxides and 4-aminoquinolines, as well as compounds active against asexual blood stages, lost most of their killing activity when parasites developed into metabolically quiescent stage V gametocytes. On the other hand, we identified compounds with consistent low nanomolar transmission-blocking activity, some of which showed cross-reactivity against asexual blood and liver stages. The data clearly emphasize substantial physiological differences between sexual and asexual parasites and provide a tool and starting points for the discovery and development of transmission-blocking drugs.

KEYWORDS:

Plasmodium; chemotherapy; gametocytes; malaria; transmission

PMID:
26749441
PMCID:
PMC4723716
DOI:
10.1016/j.chom.2015.12.001
[Indexed for MEDLINE]
Free PMC Article

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