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Nature. 2016 Oct 20;538(7625):344-349. doi: 10.1038/nature19804. Epub 2016 Sep 7.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Author information

1
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
2
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
3
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
4
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
5
School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
7
Department of Chemistry and Department of Molecular Genetics and Microbiology, Duke University, 124 Science Drive, Durham, North Carolina 27708, USA.
8
Department of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
9
Eskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
10
Eisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
11
TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
12
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, USA.
13
Eisai Co. Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
14
Department of Parasitology, Biochemical Primate Research Centre, 2280 GH Rijswijk, The Netherlands.

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.

PMID:
27602946
PMCID:
PMC5515376
DOI:
10.1038/nature19804
[Indexed for MEDLINE]
Free PMC Article

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