Open-source discovery of chemical leads for next-generation chemoprotective antimalarials | Zendy

Yevgeniya AntonovaKoch | Zendy; Stephan Meister | Zendy; Matthew Abraham | Zendy; Madeline R. Luth | Zendy; Sabine Ottilie | Zendy; Amanda K. Lukens | Zendy; Tomoyo SakataKato | Zendy; Manu Vanaerschot | Zendy; Edward Owen | Zendy; Juan Carlos Jado | Zendy; Steven P. Maher | Zendy; Jaeson Calla | Zendy; David Plouffe | Zendy; Zhong Yang | Zendy; Kaisheng Chen | Zendy; Victor Chaumeau | Zendy; Amy J. Conway | Zendy; Case W. McNamara | Zendy; Maureen Ibanez | Zendy; Kerstin Gagaring | Zendy; Fernando Neria | Zendy; Korina Eribez | Zendy; Cullin McLean Taggard | Zendy; Andrea L. Cheung | Zendy; C Lincoln | Zendy; Biniam Ambachew | Zendy; Mélanie Rouillier | Zendy; Dionicio Siegel | Zendy; François Nosten | Zendy; Dennis E. Kyle | Zendy; FranciscoJavier Gamo | Zendy; Yingyao Zhou | Zendy; Manuel Llinás | Zendy; David A. Fidock | Zendy; Dyann F. Wirth | Zendy; Jeremy N. Burrows | Zendy; Brice Campo | Zendy; Elizabeth A. Winzeler | Zendy

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Open-source discovery of chemical leads for next-generation chemoprotective antimalarials

Author(s) -

Yevgeniya AntonovaKoch,

Stephan Meister,

Matthew Abraham,

Madeline R. Luth,

Sabine Ottilie,

Amanda K. Lukens,

Tomoyo SakataKato,

Manu Vanaerschot,

Edward Owen,

Juan Carlos Jado,

Steven P. Maher,

Jaeson Calla,

David Plouffe,

Zhong Yang,

Kaisheng Chen,

Victor Chaumeau,

Amy J. Conway,

Case W. McNamara,

Maureen Ibanez,

Kerstin Gagaring,

Fernando Neria,

Korina Eribez,

Cullin McLean Taggard,

Andrea L. Cheung,

C Lincoln,

Biniam Ambachew,

Mélanie Rouillier,

Dionicio Siegel,

François Nosten,

Dennis E. Kyle,

FranciscoJavier Gamo,

Yingyao Zhou,

Manuel Llinás,

David A. Fidock,

Dyann F. Wirth,

Jeremy N. Burrows,

Brice Campo,

Elizabeth A. Winzeler

Publication year - 2018

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aat9446

Subject(s) - chemoprotective , biology , phenotypic screening , malaria , misonidazole , drug discovery , computational biology , pharmacology , in vitro , biochemistry , phenotype , gene , enzyme , immunology

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

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