title: Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.
abstract: Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.forename: David M
authors.initials: DM
authors.lastname: Plouffe
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Kuhen
authors.forename: Ghislain M C
authors.initials: GM
authors.lastname: Bonamy
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: S Whitney
authors.initials: SW
authors.lastname: Barnes
authors.forename: Selina E
authors.initials: SE
authors.lastname: Bopp
authors.forename: Rachel
authors.initials: R
authors.lastname: Borboa
authors.forename: A Taylor
authors.initials: AT
authors.lastname: Bright
authors.forename: Jianwei
authors.initials: J
authors.lastname: Che
authors.forename: Steve
authors.initials: S
authors.lastname: Cohen
authors.forename: Neekesh V
authors.initials: NV
authors.lastname: Dharia
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: Perry
authors.initials: P
authors.lastname: Gordon
authors.forename: Todd
authors.initials: T
authors.lastname: Groessl
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.forename: Marcus C S
authors.initials: MC
authors.lastname: Lee
authors.forename: Case W
authors.initials: CW
authors.lastname: McNamara
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Tae-gyu
authors.initials: TG
authors.lastname: Nam
authors.forename: Wendy
authors.initials: W
authors.lastname: Richmond
authors.forename: Jason
authors.initials: J
authors.lastname: Roland
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Patrick
authors.initials: P
authors.lastname: Froissard
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Jetsumon
authors.initials: J
authors.lastname: Sattabongkot
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.forename: Arnab
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010961:Plasmodium / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D010962:Plasmodium berghei / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D010967:Plasmodium yoelii / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D054852:Small Molecule Libraries; D034101:Sporozoites / Q000187:drug effects / Q000254:growth & development
chemical_list: D000962:Antimalarials; C568947:GNF 179; D007093:Imidazoles; D010879:Piperazines; D015800:Protozoan Proteins; D054852:Small Molecule Libraries
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