Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.

Discovery of transmission blocking compounds is an important intervention strategy necessary to eliminate and eradicate malaria. To date only a small number of drugs that inhibit gametocyte development and thereby transmission from the mosquito to the human host exist. This limitation is largely due...

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Autores principales:	Natalie G Sanders, David J Sullivan, Godfree Mlambo, George Dimopoulos, Abhai K Tripathi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4031b496e6fe41e989e99a43b44471b9
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spelling	oai:doaj.org-article:4031b496e6fe41e989e99a43b44471b92021-11-25T06:03:10ZGametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.1932-620310.1371/journal.pone.0105817https://doaj.org/article/4031b496e6fe41e989e99a43b44471b92014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25157792/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Discovery of transmission blocking compounds is an important intervention strategy necessary to eliminate and eradicate malaria. To date only a small number of drugs that inhibit gametocyte development and thereby transmission from the mosquito to the human host exist. This limitation is largely due to a lack of screening assays easily adaptable to high throughput because of multiple incubation steps or the requirement for high gametocytemia. Here we report the discovery of new compounds with gametocytocidal activity using a simple and robust SYBR Green I- based DNA assay. Our assay utilizes the exflagellation step in male gametocytes and a background suppressor, which masks the staining of dead cells to achieve healthy signal to noise ratio by increasing signal of viable parasites and subtracting signal from dead parasites. By determining the contribution of exflagellation to fluorescent signal and using appropriate cutoff values, we were able to screen for gametocytocidal compounds. After assay validation and optimization, we screened an FDA approved drug library of approximately 1500 compounds, as well as the 400 compound MMV malaria box and identified 44 gametocytocidal compounds with sub to low micromolar IC50s. Major classes of compounds with gametocytocidal activity included quaternary ammonium compounds with structural similarity to choline, acridine-like compounds similar to quinacrine and pyronaridine, as well as antidepressant, antineoplastic, and anthelminthic compounds. Top drug candidates showed near complete transmission blocking in membrane feeding assays. This assay is simple, reproducible and demonstrated robust Z-factor values at low gametocytemia levels, making it amenable to HTS for identification of novel and potent gametocytocidal compounds.Natalie G SandersDavid J SullivanGodfree MlamboGeorge DimopoulosAbhai K TripathiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e105817 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Natalie G Sanders David J Sullivan Godfree Mlambo George Dimopoulos Abhai K Tripathi Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.
description	Discovery of transmission blocking compounds is an important intervention strategy necessary to eliminate and eradicate malaria. To date only a small number of drugs that inhibit gametocyte development and thereby transmission from the mosquito to the human host exist. This limitation is largely due to a lack of screening assays easily adaptable to high throughput because of multiple incubation steps or the requirement for high gametocytemia. Here we report the discovery of new compounds with gametocytocidal activity using a simple and robust SYBR Green I- based DNA assay. Our assay utilizes the exflagellation step in male gametocytes and a background suppressor, which masks the staining of dead cells to achieve healthy signal to noise ratio by increasing signal of viable parasites and subtracting signal from dead parasites. By determining the contribution of exflagellation to fluorescent signal and using appropriate cutoff values, we were able to screen for gametocytocidal compounds. After assay validation and optimization, we screened an FDA approved drug library of approximately 1500 compounds, as well as the 400 compound MMV malaria box and identified 44 gametocytocidal compounds with sub to low micromolar IC50s. Major classes of compounds with gametocytocidal activity included quaternary ammonium compounds with structural similarity to choline, acridine-like compounds similar to quinacrine and pyronaridine, as well as antidepressant, antineoplastic, and anthelminthic compounds. Top drug candidates showed near complete transmission blocking in membrane feeding assays. This assay is simple, reproducible and demonstrated robust Z-factor values at low gametocytemia levels, making it amenable to HTS for identification of novel and potent gametocytocidal compounds.
format	article
author	Natalie G Sanders David J Sullivan Godfree Mlambo George Dimopoulos Abhai K Tripathi
author_facet	Natalie G Sanders David J Sullivan Godfree Mlambo George Dimopoulos Abhai K Tripathi
author_sort	Natalie G Sanders
title	Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.
title_short	Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.
title_full	Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.
title_fullStr	Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.
title_full_unstemmed	Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.
title_sort	gametocytocidal screen identifies novel chemical classes with plasmodium falciparum transmission blocking activity.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/4031b496e6fe41e989e99a43b44471b9
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Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.

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