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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??M) 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.

SUBMITTER: Sun W 

PROVIDER: S-EPMC3894558 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Chemical signatures and new drug targets for gametocytocidal drug development.

Sun Wei W   Tanaka Takeshi Q TQ   Magle Crystal T CT   Huang Wenwei W   Southall Noel N   Huang Ruili R   Dehdashti Seameen J SJ   McKew John C JC   Williamson Kim C KC   Zheng Wei W  

Scientific reports 20140117


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 s  ...[more]

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