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.
authors.affiliation: 1] National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States [2].
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: 1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States [2].
authors.forename: Takeshi Q
authors.initials: TQ
authors.lastname: Tanaka
authors.affiliation: Department of Biology, Loyola University Chicago, Chicago, IL 60660, United States.
authors.forename: Crystal T
authors.initials: CT
authors.lastname: Magle
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Huang
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Seameen J
authors.initials: SJ
authors.lastname: Dehdashti
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.affiliation: 1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States [2] Department of Biology, Loyola University Chicago, Chicago, IL 60660, United States.
authors.forename: Kim C
authors.initials: KC
authors.lastname: Williamson
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning / Q000379:methods; D004351:Drug Resistance; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries