Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
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.
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Nobutaka
N
Kato
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Eamon
E
Comer
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Tomoyo
T
Sakata-Kato
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
Arvind
A
Sharma
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
Manmohan
M
Sharma
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Micah
M
Maetani
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Jessica
J
Bastien
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Nicolas M
NM
Brancucci
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Joshua A
JA
Bittker
School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
Victoria
V
Corey
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
David
D
Clarke
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.|Department of Chemistry and Department of Molecular Genetics and Microbiology, Duke University, 124 Science Drive, Durham, North Carolina 27708, USA.
Emily R
ER
Derbyshire
Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
Gillian L
GL
Dornan
Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
Sandra
S
Duffy
Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Sean
S
Eckley
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Maurice A
MA
Itoe
TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
Karin M J
KM
Koolen
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Timothy A
TA
Lewis
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Ping S
PS
Lui
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Amanda K
AK
Lukens
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Emily
E
Lund
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, USA.
Sandra
S
March
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Elamaran
E
Meibalan
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Bennett C
BC
Meier
Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
Jacob A
JA
McPhail
Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Branko
B
Mitasev
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Eli L
EL
Moss
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Morgane
M
Sayes
Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Yvonne
Y
Van Gessel
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Mathias J
MJ
Wawer
Eisai Co. Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Takashi
T
Yoshinaga
Department of Parasitology, Biochemical Primate Research Centre, 2280 GH Rijswijk, The Netherlands.
Anne-Marie
AM
Zeeman
Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
Vicky M
VM
Avery
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, USA.
Sangeeta N
SN
Bhatia
Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
John E
JE
Burke
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Flaminia
F
Catteruccia
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Jon C
JC
Clardy
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Paul A
PA
Clemons
TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
Koen J
KJ
Dechering
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Jeremy R
JR
Duvall
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Michael A
MA
Foley
Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Fabian
F
Gusovsky
Department of Parasitology, Biochemical Primate Research Centre, 2280 GH Rijswijk, The Netherlands.
Clemens H M
CH
Kocken
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Matthias
M
Marti
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Marshall L
ML
Morningstar
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Benito
B
Munoz
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Daniel E
DE
Neafsey
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
Amit
A
Sharma
School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
Elizabeth A
EA
Winzeler
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Dyann F
DF
Wirth
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Christina A
CA
Scherer
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Stuart L
SL
Schreiber
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D055808:Drug Discovery; D005260:Female; D008018:Life Cycle Stages / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000469:parasitology; D008253:Macaca mulatta / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000517:prevention & control / Q000635:transmission; D008297:Male; D051379:Mice; D010652:Phenylalanine-tRNA Ligase / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development*; D012449:Safety
D000962:Antimalarials; D053961:Azabicyclo Compounds; D001384:Azetidines; C000614751:BRD7929; D010671:Phenylurea Compounds; D010652:Phenylalanine-tRNA Ligase