ArticleNature communications2017
A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.
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Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31citing papers in PubMed
8.2field-weighted citation impact, top 2% of its field
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Who cites it
31 citing papers in PubMed, 63 citations in OpenAlex.
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- Hybrid Molecules as Efficient Drugs against Multidrug-Resistant Malaria Parasites.ChemMedChem · 2025Review
- The Importance of Murine Models in Determining In Vivo Pharmacokinetics, Safety, and Efficacy in Antimalarial Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
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- Characterization of antimalarial activity of artemisinin-based hybrid drugs.Antimicrobial agents and chemotherapy · 2024Article
- Bridged 1,2,4-Trioxolanes: SnClMolecules (Basel, Switzerland) · 2023Article
- Predicting Optimal Antimalarial Drug Combinations from a Standardized Plasmodium falciparum Humanized Mouse Model.Antimicrobial agents and chemotherapy · 2023Article
- Longitudinal ex vivo and molecular trends of chloroquine and piperaquine activity against Plasmodium falciparum and P. vivax before and after introduction of artemisinin-based combination therapy in Papua, Indonesia.International journal for parasitology. Drugs and drug resistance · 2021Article
- Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205.ACS medicinal chemistry letters · 2021Article
- 5-Phenoxy Primaquine Analogs and the Tetraoxane Hybrid as Antimalarial Agents.Molecules (Basel, Switzerland) · 2021Article
- Artemisinin resistance: an important emerging clinical problem in tropical medicine.International journal of physiology, pathophysiology and pharmacology · 2021Review
- Efforts Made to Eliminate Drug-Resistant Malaria and Its Challenges.BioMed research international · 2021Review
- Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy.ACS infectious diseases · 2020Article
- Cyclic Synthetic Peroxides Inhibit Growth of Entomopathogenic FungusMolecules (Basel, Switzerland) · 2020Article
- An in vitro toolbox to accelerate anti-malarial drug discovery and development.Malaria journal · 2020Article
- Protozoan persister-like cells and drug treatment failure.Nature reviews. Microbiology · 2019Review
- Artemisinin-Based Antimalarial Drug Therapy: Molecular Pharmacology and Evolving Resistance.Tropical medicine and infectious disease · 2019Review
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Authors and funding
48 authors at 14 institutions in 8 countries.
Paul M O'NeillDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Richard K AmewuDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Susan A CharmanCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Sunil SabbaniDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Nina F GnädigDepartment of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, HHSC 1502, 701 W. 169th Street, New York, New York 10032, USA.
Judith StraimerDepartment of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, HHSC 1502, 701 W. 169th Street, New York, New York 10032, USA.
David A FidockDepartment of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, HHSC 1502, 701 W. 169th Street, New York, New York 10032, USA.ORCID 0000-0001-6753-8938
Emma R ShoreDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Natalie L RobertsDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Michael H-L WongDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
W David HongDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Chandrakala PidathalaDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Chris RileyDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Ben MurphyDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Ghaith AljayyoussiResearch Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
Francisco Javier GamoTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
Laura SanzTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
Janneth RodriguesTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
Carolina Gonzalez CortesTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
Esperanza HerrerosTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
Iñigo Angulo-BarturénTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
María Belén Jiménez-DíazTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
Santiago Ferrer BazagaTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
María Santos Martínez-MartínezTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
Brice CampoMedicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
Raman SharmaResearch Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
Eileen RyanCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
David M ShacklefordCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Simon CampbellMedicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
Dennis A SmithMedicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
Grennady WirjanataGlobal and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, P.O. Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia.
Rintis NoviyantiEijkman Institute for Molecular Biology, Jl. Diponegoro 69, 10430 Jakarta, Indonesia.
Ric N PriceGlobal and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, P.O. Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia.
Jutta MarfurtGlobal and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, P.O. Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia.
Michael J PalmerMedicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
Ian M CoppleDepartment of Pharmacology, School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE UK.
Amy E MercerDepartment of Pharmacology, School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE UK.
Andrea RueckerDepartment of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK.
Michael J DelvesDepartment of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK.
Robert E SindenDepartment of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK.
Peter SieglMedicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
Jill DaviesResearch Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
Rosemary RochfordDepartment of Immunology and Microbiology, University of Colorado, Aurora Colorado, CO 80045, USA.
Clemens H M KockenDepartment of Parasitology, Biomedical Primate Research Centre, P. O. Box 3306, 2280 GH Rijswijk, The Netherlands.
Anne-Marie ZeemanDepartment of Parasitology, Biomedical Primate Research Centre, P. O. Box 3306, 2280 GH Rijswijk, The Netherlands.
Gemma L NixonDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Giancarlo A BiaginiResearch Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
Stephen A WardResearch Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
University of Liverpool · GBGlaxoSmithKline (Spain) · ESLiverpool School of Tropical Medicine · GBMedicines for Malaria Venture · CHMonash University · AUBiomedical Primate Research Centre · NLCharles Darwin University · AUColumbia University · USImperial College London · GBAngkor Hospital for Children · KHColumbia University Irving Medical Center · USEijkman Institute for Molecular Biology · IDUniversity of Colorado Anschutz Medical Campus · USUniversity of Oxford · GB
Funding
Defining P. falciparum resistance to artemisinin-based combination therapiesR01AI109023 · NIAID · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI FIDOCK, DAVID A · 2014 to 2025
$4.4MMedical Research Council G0700654Medical Research Council MC_PC_12017Medical Research Council MC_PC_13069Medical Research Council MC_PC_14111Medical Research Council MC_PC_15040Medical Research Council MC_PC_16052Medical Research Council MR/L000644/1NIAID NIH HHS R01 AI109023Wellcome Trust 200909/Z/16/Z
Abstract
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
Indexed as
AnimalsAntimalarialsArtemisininsDogsDose-Response Relationship, DrugDrug ResistanceErythrocytesFemaleHalf-LifeHumansMaleMiceMice, Inbred NODMice, SCIDMutationPlasmodium falciparumAntimalarialsartemisininArtemisininsProtozoan ProteinsTetraoxanes
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