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Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Author

Listed:
  • Nobutaka Kato

    (Broad Institute of Harvard and MIT)

  • Eamon Comer

    (Broad Institute of Harvard and MIT)

  • Tomoyo Sakata-Kato

    (Harvard T.H. Chan School of Public Health)

  • Arvind Sharma

    (Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology)

  • Manmohan Sharma

    (Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology)

  • Micah Maetani

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Jessica Bastien

    (Broad Institute of Harvard and MIT)

  • Nicolas M. Brancucci

    (Harvard T.H. Chan School of Public Health)

  • Joshua A. Bittker

    (Broad Institute of Harvard and MIT)

  • Victoria Corey

    (School of Medicine, University of California, San Diego)

  • David Clarke

    (Harvard T.H. Chan School of Public Health)

  • Emily R. Derbyshire

    (Broad Institute of Harvard and MIT
    Harvard Medical School
    Duke University)

  • Gillian L. Dornan

    (University of Victoria)

  • Sandra Duffy

    (Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University)

  • Sean Eckley

    (Eisai Inc., 4 Corporate Drive)

  • Maurice A. Itoe

    (Harvard T.H. Chan School of Public Health)

  • Karin M. J. Koolen

    (TropIQ Health Sciences, Geert Grooteplein 28)

  • Timothy A. Lewis

    (Broad Institute of Harvard and MIT)

  • Ping S. Lui

    (Harvard T.H. Chan School of Public Health)

  • Amanda K. Lukens

    (Broad Institute of Harvard and MIT
    Harvard T.H. Chan School of Public Health)

  • Emily Lund

    (Harvard T.H. Chan School of Public Health)

  • Sandra March

    (Broad Institute of Harvard and MIT
    Massachusetts Institute of Technology)

  • Elamaran Meibalan

    (Harvard T.H. Chan School of Public Health)

  • Bennett C. Meier

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Jacob A. McPhail

    (University of Victoria)

  • Branko Mitasev

    (Eisai Inc., 4 Corporate Drive)

  • Eli L. Moss

    (Broad Institute of Harvard and MIT)

  • Morgane Sayes

    (Broad Institute of Harvard and MIT)

  • Yvonne Van Gessel

    (Eisai Inc., 4 Corporate Drive)

  • Mathias J. Wawer

    (Broad Institute of Harvard and MIT)

  • Takashi Yoshinaga

    (Eisai Co. Ltd, 5-1-3 Tokodai, Tsukuba)

  • Anne-Marie Zeeman

    (Biochemical Primate Research Centre)

  • Vicky M. Avery

    (Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University)

  • Sangeeta N. Bhatia

    (Broad Institute of Harvard and MIT
    Massachusetts Institute of Technology)

  • John E. Burke

    (University of Victoria)

  • Flaminia Catteruccia

    (Harvard T.H. Chan School of Public Health)

  • Jon C. Clardy

    (Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Paul A. Clemons

    (Broad Institute of Harvard and MIT)

  • Koen J. Dechering

    (TropIQ Health Sciences, Geert Grooteplein 28)

  • Jeremy R. Duvall

    (Broad Institute of Harvard and MIT)

  • Michael A. Foley

    (Broad Institute of Harvard and MIT)

  • Fabian Gusovsky

    (Eisai Inc., 4 Corporate Drive)

  • Clemens H. M. Kocken

    (Biochemical Primate Research Centre)

  • Matthias Marti

    (Harvard T.H. Chan School of Public Health)

  • Marshall L. Morningstar

    (Broad Institute of Harvard and MIT)

  • Benito Munoz

    (Broad Institute of Harvard and MIT)

  • Daniel E. Neafsey

    (Broad Institute of Harvard and MIT)

  • Amit Sharma

    (Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology)

  • Elizabeth A. Winzeler

    (School of Medicine, University of California, San Diego)

  • Dyann F. Wirth

    (Broad Institute of Harvard and MIT
    Harvard T.H. Chan School of Public Health)

  • Christina A. Scherer

    (Broad Institute of Harvard and MIT)

  • Stuart L. Schreiber

    (Broad Institute of Harvard and MIT
    Harvard University)

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.

Suggested Citation

  • Nobutaka Kato & Eamon Comer & Tomoyo Sakata-Kato & Arvind Sharma & Manmohan Sharma & Micah Maetani & Jessica Bastien & Nicolas M. Brancucci & Joshua A. Bittker & Victoria Corey & David Clarke & Emily , 2016. "Diversity-oriented synthesis yields novel multistage antimalarial inhibitors," Nature, Nature, vol. 538(7625), pages 344-349, October.
    • Handle: RePEc:nat:nature:v:538:y:2016:i:7625:d:10.1038_nature19804
    DOI: 10.1038/nature19804
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    Citations

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    Cited by:

    1. Selina Bopp & Charisse Flerida A. Pasaje & Robert L. Summers & Pamela Magistrado-Coxen & Kyra A. Schindler & Victoriano Corpas-Lopez & Tomas Yeo & Sachel Mok & Sumanta Dey & Sebastian Smick & Armiyaw , 2023. "Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Liam Hudson & Jeremy W. Mason & Matthias V. Westphal & Matthieu J. R. Richter & Jonathan R. Thielman & Bruce K. Hua & Christopher J. Gerry & Guoqin Xia & Heather L. Osswald & John M. Knapp & Zher Yin , 2023. "Diversity-oriented synthesis encoded by deoxyoligonucleotides," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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