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Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
Kato, Nobutaka; Comer, Eamon; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M; Bittker, Joshua A; Corey, Victoria; Clarke, David; Derbyshire, Emily R; Dornan, Gillian L; Duffy, Sandra; Eckley, Sean; Itoe, Maurice A; Koolen, Karin M J; Lewis, Timothy A; Lui, Ping S; Lukens, Amanda K; Lund, Emily; March, Sandra; Meibalan, Elamaran; Meier, Bennett C; McPhail, Jacob A; Mitasev, Branko; Moss, Eli L; Sayes, Morgane; Van Gessel, Yvonne; Wawer, Mathias J; Yoshinaga, Takashi; Zeeman, Anne-Marie; Avery, Vicky M; Bhatia, Sangeeta N; Burke, John E; Catteruccia, Flaminia; Clardy, Jon C; Clemons, Paul A; Dechering, Koen J; Duvall, Jeremy R; Foley, Michael A; Gusovsky, Fabian; Kocken, Clemens H M; Marti, Matthias; Morningstar, Marshall L; Munoz, Benito; Neafsey, Daniel E; Sharma, Amit; Winzeler, Elizabeth A; Wirth, Dyann F.
Affiliation
  • Kato N; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Comer E; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Sakata-Kato T; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Sharma A; Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
  • Sharma M; Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
  • Maetani M; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Bastien J; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
  • Brancucci NM; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Bittker JA; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Corey V; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Clarke D; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
  • Derbyshire ER; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Dornan GL; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Duffy S; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
  • Eckley S; Department of Chemistry and Department of Molecular Genetics and Microbiology, Duke University, 124 Science Drive, Durham, North Carolina 27708, USA.
  • Itoe MA; Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
  • Koolen KM; Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
  • Lewis TA; Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
  • Lui PS; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Lukens AK; TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
  • Lund E; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • March S; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Meibalan E; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Meier BC; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • McPhail JA; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Mitasev B; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Moss EL; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, USA.
  • Sayes M; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Van Gessel Y; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Wawer MJ; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
  • Yoshinaga T; Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
  • Zeeman AM; Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
  • Avery VM; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Bhatia SN; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Burke JE; Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
  • Catteruccia F; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Clardy JC; Eisai Co. Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
  • Clemons PA; Department of Parasitology, Biochemical Primate Research Centre, 2280 GH Rijswijk, The Netherlands.
  • Dechering KJ; Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
  • Duvall JR; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Foley MA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, USA.
  • Gusovsky F; Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
  • Kocken CH; Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
  • Marti M; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Morningstar ML; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
  • Munoz B; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Neafsey DE; TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
  • Sharma A; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Winzeler EA; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Wirth DF; Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Nature ; 538(7625): 344-349, 2016 Oct 20.
Article in En | MEDLINE | ID: mdl-27602946
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Plasmodium falciparum / Azetidines / Malaria, Falciparum / Drug Discovery / Life Cycle Stages / Antimalarials Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nature Year: 2016 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Plasmodium falciparum / Azetidines / Malaria, Falciparum / Drug Discovery / Life Cycle Stages / Antimalarials Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nature Year: 2016 Document type: Article Affiliation country: