ArticleNature2016
Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
Erratum issuedOpen access · greenAbstract read
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Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 125 papers.
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125citing papers in PubMed
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Who cites it
125 citing papers in PubMed, 262 citations in OpenAlex.
- An assay to quantify sexual commitment and stage conversion in the human malaria parasite Plasmodium falciparum.Nature protocols · 2026Review
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- Structure-Guided Optimization of Novel Inhibitors ofJournal of medicinal chemistry · 2026Article
- A single valine to leucine switch disrupts Plasmodium falciparum AP2-G DNA binding and reveals GDV1's role in ap2-g activation.Nature communications · 2026Article
- Multi-MoleScale: a multi-scale approach for molecular property prediction with graph contrastive and sequence learning.Journal of cheminformatics · 2025Article
- Asymmetric formal [1 + 2 + 2]-cycloaddition of diazoamides with enamines and carbonyl compounds.Nature communications · 2025Article
- Optimization of 2,8-Diaryl-1,5-naphthyridines asJournal of medicinal chemistry · 2025Article
- Disruption of P. falciparum amino acid transporter elevates intracellular proline and induces resistance to Prolyl-tRNA synthetase inhibitors.Cell chemical biology · 2025Article
- Improved Bicyclic Pyrrolidine Analogues InhibitJournal of medicinal chemistry · 2025Article
- Novel Inhibitors ofJournal of medicinal chemistry · 2025Article
- Covalent inhibition ofiScience · 2025Article
- Revisiting theNPJ drug discovery · 2025Article
- Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes.Cell chemical biology · 2024Article
- To quest new targets ofJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2024Review
- Screening the Global Health Priority Box against Plasmodium berghei liver stage parasites using an inexpensive luciferase detection protocol.Malaria journal · 2024Article
- Molecular complexity as a driving force for the advancement of organic synthesis.Nature reviews. Chemistry · 2024Review
- ATP mimetics targeting prolyl-tRNA synthetases as a new avenue for antimalarial drug development.iScience · 2024Article
- Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Intestinal cDC1s provide cues required for CD4+ T cell-mediated resistance to Cryptosporidium.The Journal of experimental medicine · 2024Article
- Bicyclic Pyrrolidine Inhibitors ofACS infectious diseases · 2024Article
65 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
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Authors and funding
52 authors at 11 institutions in 6 countries.
Nobutaka KatoBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Eamon ComerBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Tomoyo Sakata-KatoHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Arvind SharmaMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
Manmohan SharmaMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
Micah MaetaniBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Jessica BastienBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Nicolas M BrancucciHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Joshua A BittkerBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Victoria CoreySchool of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
David ClarkeHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Emily R DerbyshireBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Gillian L DornanDepartment of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
Sandra DuffyEskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
Sean EckleyEisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Maurice A ItoeHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Karin M J KoolenTropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
Timothy A LewisBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Ping S LuiHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Amanda K LukensBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Emily LundHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Sandra MarchBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Elamaran MeibalanHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Bennett C MeierBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Jacob A McPhailDepartment of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
Branko MitasevEisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Eli L MossBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Morgane SayesBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Yvonne Van GesselEisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Mathias J WawerBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Takashi YoshinagaEisai Co. Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Anne-Marie ZeemanDepartment of Parasitology, Biochemical Primate Research Centre, 2280 GH Rijswijk, The Netherlands.
Vicky M AveryEskitis Institute for Drug Discovery, Griffith University, Nathan Campus, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
Sangeeta N BhatiaBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
John E BurkeDepartment of Biochemistry and Microbiology, University of Victoria, 270 Petch Hall, Victoria, British Colombia V8P 5C2, Canada.
Flaminia CatterucciaHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Jon C ClardyBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Paul A ClemonsBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Koen J DecheringTropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
Jeremy R DuvallBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Michael A FoleyBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Fabian GusovskyEisai Inc., 4 Corporate Drive, Andover, Massachusetts 01810, USA.
Clemens H M KockenDepartment of Parasitology, Biochemical Primate Research Centre, 2280 GH Rijswijk, The Netherlands.
Matthias MartiHarvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, Massachusetts 02115, USA.
Marshall L MorningstarBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Benito MunozBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Daniel E NeafseyBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Amit SharmaMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
Elizabeth A WinzelerSchool of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
Dyann F WirthBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Christina A SchererBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Stuart L SchreiberBroad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Broad Institute · USHarvard University · USEisai (United States) · USInternational Centre for Genetic Engineering and Biotechnology · INUniversity of Victoria · CABiomedical Primate Research Centre · NLGriffith University · AUTropIQ Health Sciences · NLUniversity of California, San Diego · USEisai (Japan) · JPMassachusetts Institute of Technology · US
Funding
Training Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6MTargeting the Mitochondrion of P. falciparumR01AI093716 · NIAID · HARVARD SCHOOL OF PUBLIC HEALTH · PI WIRTH, DYANN F · 2012 to 2020
$4.8MDiscovery of chemically validated malaria liver stage targetsR01AI090141 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WINZELER, ELIZABETH A · 2011 to 2019
$3.4MDefining the targets of broad intervention antimalarial agentsR01AI103058 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WINZELER, ELIZABETH A · 2013 to 2016
$2.6MNIAID NIH HHS R01 AI090141NIAID NIH HHS R01 AI093716NIAID NIH HHS R01 AI103058NIGMS NIH HHS T32 GM008666Wellcome Trust
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.
Indexed as
Drug DiscoveryAnimalsAntimalarialsAzabicyclo CompoundsAzetidinesCytosolDisease Models, AnimalFemaleLife Cycle StagesLiverMacaca mulattaMalaria, FalciparumMaleMicePhenylalanine-tRNA LigasePhenylurea CompoundsAntimalarialsAzabicyclo CompoundsAzetidinesBRD7929Phenylalanine-tRNA LigasePhenylurea Compounds
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.