Abstract

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.

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Data deposits

The whole-genome sequencing analysis data in this study have been deposited to the Short Read Archive; accession code SRP064988 and the x-ray crystal structure data for BRD7929 have been deposited to the Cambridge Structural Database: deposition number 1429949.

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Acknowledgements

This work was supported in part by the Bill and Melinda Gates Foundation (grant OPP1032518 to S.L.S., grant OPP1054480 to E.A.W. and D.F.W., grant OPP1023607 to S.N.B.), the Global Health Innovative Technology Fund (grant G2014-107 to S.L.S.), Medicines for Malaria Venture and the Wellcome Trust (grant WT078285 to C.H.M.K.), a New Investigator and Open Operating Grant from Canadian Institute of Health Research (grant FRN 142393 to J.E.B.) and Medicines for Malaria Venture (grant 12-2400 to V.M.A.). S.L.S. is an Investigator at the Howard Hughes Medical Institute. Mi.M. was supported by a fellowship from the National Science Foundation (DGE1144152). The authors thank R. Elliott, K. Duncan, and O. Vandal as well as J. Burrows, J. Duffy, F. Escudié and colleagues for discussions and access to invaluable scientific and experimental resources; K. Emmith for assistance with data processing and management; I. Goldowitz for assistance with establishing a gametocyte assay; N. van der Werff for technical assistance with the P. cynomolgi assay; J. Kotz and B. Melillo for discussions and assistance with the manuscript; J. Pu, M. Leighty, B. Braibant, S. LeQuement and J. Beaudoin for assistance with compound synthesis; E. Garcia-Rivera for assistance with molecular modelling; A. Hakura for performing the Ames test; Broad Institute Comparative Medicine Platform and Facility for assistance with animal studies; and the Broad Institute Compound Management and analytical teams for assistance with compound access and characterization. We also acknowledge WuXi AppTec and ChemPartner Co., Ltd for in vitro and in vivo pharmacokinetics assays, and Cyprotek for the phototoxicity analysis. P. falciparum scDHODH transgenic strain was a gift from A. B. Vaidya, P. falciparum 3D7HLH strain from D. Fidock and P. falciparum NF54HT-GFP-luc from S. H. Kappe.

Author information

Author notes

    • Nobutaka Kato
    •  & Eamon Comer

    These authors contributed equally to this work.

Affiliations

  1. Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA

    • Nobutaka Kato
    • , Eamon Comer
    • , Micah Maetani
    • , Jessica Bastien
    • , Joshua A. Bittker
    • , Emily R. Derbyshire
    • , Timothy A. Lewis
    • , Amanda K. Lukens
    • , Sandra March
    • , Bennett C. Meier
    • , Eli L. Moss
    • , Morgane Sayes
    • , Mathias J. Wawer
    • , Sangeeta N. Bhatia
    • , Jon C. Clardy
    • , Paul A. Clemons
    • , Jeremy R. Duvall
    • , Michael A. Foley
    • , Marshall L. Morningstar
    • , Benito Munoz
    • , Daniel E. Neafsey
    • , Dyann F. Wirth
    • , Christina A. Scherer
    •  & Stuart L. Schreiber
  2. Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA

    • Tomoyo Sakata-Kato
    • , Nicolas M. Brancucci
    • , David Clarke
    • , Maurice A. Itoe
    • , Ping S. Lui
    • , Amanda K. Lukens
    • , Emily Lund
    • , Elamaran Meibalan
    • , Flaminia Catteruccia
    • , Matthias Marti
    •  & Dyann F. Wirth
  3. Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India

    • Arvind Sharma
    • , Manmohan Sharma
    •  & Amit Sharma
  4. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA

    • Micah Maetani
    • , Bennett C. Meier
    •  & Stuart L. Schreiber
  5. School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, USA

    • Victoria Corey
    •  & Elizabeth A. Winzeler
  6. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA

    • Emily R. Derbyshire
    •  & Jon C. Clardy
  7. Department of Chemistry and Department of Molecular Genetics and Microbiology, Duke University, 124 Science Drive, Durham, North Carolina 27708, USA

    • Emily R. Derbyshire
  8. Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada

    • Gillian L. Dornan
    • , Jacob A. McPhail
    •  & John E. Burke
  9. Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia

    • Sandra Duffy
    •  & Vicky M. Avery
  10. Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA

    • Sean Eckley
    • , Branko Mitasev
    • , Yvonne Van Gessel
    •  & Fabian Gusovsky
  11. TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands

    • Karin M. J. Koolen
    •  & Koen J. Dechering
  12. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, USA

    • Sandra March
    •  & Sangeeta N. Bhatia
  13. Eisai Co. Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan

    • Takashi Yoshinaga
  14. Department of Parasitology, Biochemical Primate Research Centre, 2280 GH Rijswijk, The Netherlands

    • Anne-Marie Zeeman
    •  & Clemens H. M. Kocken

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Contributions

The author contributions are detailed in the Supplementary Information.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stuart L. Schreiber.

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https://doi.org/10.1038/nature19804

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