Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

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 R. Derbyshire, Gillian L. Dornan, Sandra Duffy, Sean Eckley, Maurice A. Itoe, Karin M. J. Koolen, Timothy A. Lewis, Ping S. Lui, Amanda K. Lukens, Emily Lund, Sandra March, Elamaran Meibalan, Bennett C. Meier, Jacob A. McPhail, Branko Mitasev, Eli L. Moss, Morgane Sayes, Yvonne Van Gessel, Mathias J. Wawer, Takashi Yoshinaga, Anne-Marie Zeeman, Vicky M. Avery, Sangeeta N. Bhatia, John E. Burke, Flaminia Catteruccia, Jon C. Clardy, Paul A. Clemons, Koen J. Dechering, Jeremy R. Duvall, Michael A. Foley, Fabian Gusovsky, Clemens H. M. Kocken, Matthias Marti, Marshall L. Morningstar, Benito Munoz, Daniel E. Neafsey, Amit Sharma, Elizabeth A. Winzeler, Dyann F. Wirth, Christina A. Scherer and Stuart L. Schreiber ()
Additional contact information
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
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
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
Emily Lund: Harvard T.H. Chan School of Public Health
Sandra March: Broad Institute of Harvard and MIT
Elamaran Meibalan: Harvard T.H. Chan School of Public Health
Bennett C. Meier: Broad Institute of Harvard and MIT
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
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
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
Christina A. Scherer: Broad Institute of Harvard and MIT
Stuart L. Schreiber: Broad Institute of Harvard and MIT

Nature, 2016, vol. 538, issue 7625, 344-349

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19804

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