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Nature DOI:10.1038/nature19804

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Publication TypeJournal Article
Year of Publication2016
AuthorsKato, N, Comer, E, Sakata-Kato, T, Sharma, A, Sharma, M, Maetani, M, Bastien, J, Brancucci, NM, Bittker, JA, Corey, V, Clarke, D, Derbyshire, ER, Dornan, GL, Duffy, S, Eckley, S, Itoe, MA, Koolen, KMJ, Lewis, TA, Lui, PS, Lukens, AK, Lund, E, March, S, Meibalan, E, Meier, BC, McPhail, JA, Mitasev, B, Moss, EL, Sayes, M, Van Gessel, Y, Wawer, MJ, Yoshinaga, T, Zeeman, A-M, Avery, VM, Bhatia, SN, Burke, JE, Catteruccia, F, Clardy, JC, Clemons, PA, Dechering, KJ, Duvall, JR, Foley, MA, Gusovsky, F, Kocken, CHM, Marti, M, Morningstar, ML, Munoz, B, Neafsey, DE, Sharma, A, Winzeler, EA, Wirth, DF, Scherer, CA, Schreiber, SL
Date Published2016 Oct 20
KeywordsAnimals, Antimalarials, Azabicyclo Compounds, Azetidines, Cytosol, Disease Models, Animal, Drug Discovery, Female, Life Cycle Stages, Liver, Macaca mulatta, Malaria, Falciparum, Male, Mice, Phenylalanine-tRNA Ligase, Phenylurea Compounds, Plasmodium falciparum, Safety

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.


Alternate JournalNature
PubMed ID27602946
PubMed Central IDPMC5515376
Grant ListR01 AI090141 / AI / NIAID NIH HHS / United States
R01 AI103058 / AI / NIAID NIH HHS / United States
R01 AI093716 / AI / NIAID NIH HHS / United States
T32 GM008666 / GM / NIGMS NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom