New antimalarial agents and drug targets identified from a screen against plasmodium falciparum gametocytes

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCATS	CHEMBIO-4

* FARE Award Winner

Authors

• W. Sun
• T.Q. Tanaka
• C.T. Magle
• W Huang
• N Southall
• R Huang
• S.J. Dehdashti
• J.C. McKew
• K.C. Williamson
• W. Zheng

Abstract

Malaria continues to be a life-threatening disease, causing 219 million cases and 660, 000 deaths in 2010. Eliminating malaria transmission is an essential goal of eradicating malaria eventually. Sexual stage P. falciparum gametocytes in patients have a lifespan of over 3 weeks that are responsible for spread of malaria from person to person. However, gametocytes are not cleared effectively by current antimalarial agents except primaquine which is not widely used because it causes hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. Consequently, treatment with current antimalarial drugs often results in asymptomatic carriers who remain infectious for weeks after the clearance of asexual parasites. Here, we report the identification of 27 potent gametocytocidal compounds from a screen using a P. falciparum gametocyte viability assay. All these compounds were active against three strains of gametocytes. Cheminformatics analysis revealed chemical signatures of approved drugs on sexual and asexual stages of P. falciparum. Torin 2, a lead compound, exhibited nanomolar potency against gametocytes in vitro and completely blocked gametocyte transmission in a mouse model. Furthermore, we identified three gametocyte proteins as potential molecular targets of Torin 2 using affinity pull-down. These results provide critical new leads and potential targets for blocking malaria transmission.

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