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

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          Summary

          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.

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          Highlights

          • Developed SaLSSA, a serum-free one-step assay for malaria transmission-blocking activity

          • 13,983 known and new compounds analyzed by SaLSSA

          • >90% known antimalarial drugs do not show activity against late-stage gametocytes

          • Compounds with consistent low nanomolar transmission-blocking activity identified

          Abstract

          Preventing human-mosquito transmission is important for malaria control. Plouffe et al. developed SaLSSA, a one-step high-throughput assay to screen for malaria transmission-blocking activity. A large panel of known and new small molecules was analyzed by SaLSSA. This provides starting points for the discovery and development of transmission-blocking drugs.

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          Most cited references54

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          Spiroindolones, a potent compound class for the treatment of malaria.

          Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
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            Regulation of sexual development of Plasmodium by translational repression.

            G Mair (2006)
            Translational repression of messenger RNAs (mRNAs) plays an important role in sexual differentiation and gametogenesis in multicellular eukaryotes. Translational repression and mRNA turnover were shown to influence stage-specific gene expression in the protozoan Plasmodium. The DDX6-class RNA helicase, DOZI (development of zygote inhibited), is found in a complex with mRNA species in cytoplasmic bodies of female, blood-stage gametocytes. These translationally repressed complexes are normally stored for translation after fertilization. Genetic disruption of pbdozi inhibits the formation of the ribonucleoprotein complexes, and instead, at least 370 transcripts are diverted to a degradation pathway.
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              Guidelines for the treatment of malaria

              (2015)
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                Author and article information

                Contributors
                Journal
                Cell Host Microbe
                Cell Host Microbe
                Cell Host & Microbe
                Cell Press
                1931-3128
                1934-6069
                13 January 2016
                13 January 2016
                : 19
                : 1
                : 114-126
                Affiliations
                [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 ]Department of Chemistry and Chemical Biology, Harvard University, 7 Cambridge Center, Cambridge, MA 02142, USA
                Author notes
                []Corresponding author ewinzeler@ 123456ucsd.edu
                [7]

                Co-first author

                [8]

                Present address: EMD Serono Research and Development Institute, Billerica, MA 02370, USA

                Article
                S1931-3128(15)00493-X
                10.1016/j.chom.2015.12.001
                4723716
                26749441
                a90f9c17-74bb-45e4-be87-4fd7881d4771
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 4 September 2015
                : 13 November 2015
                : 11 December 2015
                Categories
                Resource

                Microbiology & Virology
                transmission,malaria,chemotherapy,gametocytes,plasmodium
                Microbiology & Virology
                transmission, malaria, chemotherapy, gametocytes, plasmodium

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