Chemical signatures and new drug targets for gametocytocidal drug development

Wei Sun; Takeshi Q. Tanaka; Crystal T. Magle; Wenwei Huang; Noel Southall; Ruili Huang; Seameen J. Dehdashti; John C. McKew; Kim C. Williamson; Wei Zheng

doi:10.1038/srep03743

Chemical signatures and new drug targets for gametocytocidal drug development

Wei Sun, Takeshi Q. Tanaka, Crystal T. Magle, Wenwei Huang, Noel Southall, Ruili Huang, Seameen J. Dehdashti, John C. McKew, Kim C. Williamson^*, Wei Zheng

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

Abstract

Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC₅₀ < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC₅₀ = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.

Original language	English
Article number	3743
Journal	Scientific Reports
Volume	4
DOIs	https://doi.org/10.1038/srep03743
State	Published - 1 Apr 2015
Externally published	Yes

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10.1038/srep03743

Cite this

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title = "Chemical signatures and new drug targets for gametocytocidal drug development",

abstract = "Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.",

author = "Wei Sun and Tanaka, {Takeshi Q.} and Magle, {Crystal T.} and Wenwei Huang and Noel Southall and Ruili Huang and Dehdashti, {Seameen J.} and McKew, {John C.} and Williamson, {Kim C.} and Wei Zheng",

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AU - Sun, Wei

AU - Tanaka, Takeshi Q.

AU - Magle, Crystal T.

AU - Huang, Wenwei

AU - Southall, Noel

AU - Huang, Ruili

AU - Dehdashti, Seameen J.

AU - McKew, John C.

AU - Williamson, Kim C.

AU - Zheng, Wei

PY - 2015/4/1

Y1 - 2015/4/1

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AB - Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.

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