title: High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission.
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.
authors.affiliation: The Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Plouffe
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wree
authors.affiliation: 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.
authors.forename: Alan Y
authors.initials: AY
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Fengwu
authors.initials: F
authors.lastname: Li
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Kailash
authors.initials: K
authors.lastname: Patra
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Aristea
authors.initials: A
authors.lastname: Lubar
authors.affiliation: 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.
authors.forename: Shinji L
authors.initials: SL
authors.lastname: Okitsu
authors.affiliation: 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.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Flannery
authors.affiliation: Broad Institute, 415 Main Street, Cambridge MA 02142.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.affiliation: The Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Tanaseichuk
authors.affiliation: Broad Institute, 415 Main Street, Cambridge MA 02142.
authors.forename: Eamon
authors.initials: E
authors.lastname: Comer
authors.affiliation: The Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: The Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.affiliation: The Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Medicines for Malaria Venture (MMV), PO Box 1826, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.affiliation: Broad Institute, 415 Main Street, Cambridge MA 02142; Department of Chemistry and Chemical Biology, Harvard University, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Broad Institute, 415 Main Street, Cambridge MA 02142.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Scherer
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vinetz
authors.affiliation: 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.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008288:Malaria / Q000469:parasitology* / Q000635:transmission; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology
chemical_list: D000962:Antimalarials
keywords: Plasmodium; chemotherapy; gametocytes; malaria; transmission