ArticleNature communications2022
Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23citing papers in PubMed
2.4field-weighted citation impact, top 10% of its field
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
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- Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance.Nature communications · 2026Article
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- Minimum inoculum of resistance assay for evaluating for anti-toxoplasmosis compounds that target phenyl alanine tRNA synthetase.bioRxiv : the preprint server for biology · 2026Article
- Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor.Nature communications · 2025Article
- Thiazole substitution of a labile amide bond-a new option toward antiplasmodial pantothenamide-mimics.Antimicrobial agents and chemotherapy · 2025Article
- An improved multiplex RT-quantitative PCR assay can reveal sex-specific activity of transmission-blocking drugs on ex vivo gametocytes from Plasmodium falciparum asymptomatic infections.The Journal of antimicrobial chemotherapy · 2025Article
- Antimalarial Drug Discovery from Natural and Synthetic Sources.Current medicinal chemistry · 2025Review
- Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials.Nature communications · 2024Article
- Defining the next generation of severe malaria treatment: a target product profile.Malaria journal · 2024Review
- Highly Regioselective Protecting-Group-Free Synthesis of the Antimalarial Drug MMV693183.Organic process research & development · 2024Article
- Molecular mechanisms of mitochondria-mediated ferroptosis: a potential target for antimalarial interventions.Frontiers in cell and developmental biology · 2024Review
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- Starving the Beast: Limiting Coenzyme A Biosynthesis to Prevent Disease and Transmission in Malaria.International journal of molecular sciences · 2023Review
- A versatile Plasmodium falciparum reporter line expressing NanoLuc enables highly sensitive multi-stage drug assays.Communications biology · 2023Article
- Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline.Microbiology spectrum · 2023Article
- Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation.Nature communications · 2023Article
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Authors and funding
45 authors at 17 institutions in 8 countries.
Laura E de VriesDepartment of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.ORCID 0000-0002-3930-3311
Patrick A M JansenDepartment of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Catalina BarceloMedicines for Malaria Venture, Geneva, Switzerland.
Justin MunroDepartment of Chemistry and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA, USA.
Julie M J VerhoefDepartment of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.ORCID 0000-0002-0573-1801
Charisse Flerida A PasajeDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.ORCID 0000-0002-9780-3680
Kelly RubianoDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA.
Josefine StriepenDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0003-4673-3114
Nada AblaMedicines for Malaria Venture, Geneva, Switzerland.
Luuk BerningTropIQ Health Sciences, Nijmegen, The Netherlands.ORCID 0000-0001-8802-8195
Judith M BolscherTropIQ Health Sciences, Nijmegen, The Netherlands.
Claudia Demarta-GatsiMedicines for Malaria Venture, Geneva, Switzerland.ORCID 0000-0002-9610-2962
Rob W M HendersonTropIQ Health Sciences, Nijmegen, The Netherlands.
Tonnie HuijsTropIQ Health Sciences, Nijmegen, The Netherlands.
Karin M J KoolenTropIQ Health Sciences, Nijmegen, The Netherlands.
Patrick K TumwebazeInfectious Diseases Research Collaboration, Kampala, Uganda.
Tomas YeoDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0003-2923-6060
Anna C C AguiarSao Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo, Brazil, São Carlos, SP, Brazil.
Iñigo Angulo-BarturenThe Art of Discovery, Derio, Spain.ORCID 0000-0002-8800-8132
Alisje ChurchyardDepartment of Life Sciences, Imperial College London, South Kensington, London, United Kingdom.ORCID 0000-0002-4726-6397
Jake BaumDepartment of Life Sciences, Imperial College London, South Kensington, London, United Kingdom.ORCID 0000-0002-0275-352X
Benigno Crespo FernándezGlobal Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
Aline FuchsMedicines for Malaria Venture, Geneva, Switzerland.
Francisco-Javier GamoGlobal Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
Rafael V C GuidoSao Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo, Brazil, São Carlos, SP, Brazil.ORCID 0000-0002-7187-0818
María Belén Jiménez-DiazThe Art of Discovery, Derio, Spain.
Dhelio B PereiraResearch Center for Tropical Medicine of Rondonia, Porto Velho, Brazil.ORCID 0000-0002-7761-5498
Rosemary RochfordDepartment of Immunology and Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA.
Camille RoeschMalaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.ORCID 0000-0002-5119-0655
Laura M SanzGlobal Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain.ORCID 0000-0003-0796-5211
Graham TrevittSygnature Discovery, Nottingham, United Kingdom.
Benoit WitkowskiMalaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
Sergio WittlinSwiss Tropical and Public Health Institute, Basel, Switzerland.
Roland A CooperDepartment of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, USA.
Philip J RosenthalDepartment of Medicine, University of California, San Francisco, CA, USA.
Robert W SauerweinDepartment of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Joost SchalkwijkDepartment of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.ORCID 0000-0002-1308-1319
Pedro H H HermkensHermkens Pharma Consultancy, Oss, The Netherlands.
Roger V BonnertMedicines for Malaria Venture, Geneva, Switzerland.
Brice CampoMedicines for Malaria Venture, Geneva, Switzerland.ORCID 0000-0002-6425-5577
David A FidockDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0001-6753-8938
Manuel LlinásDepartment of Chemistry and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA, USA.ORCID 0000-0002-6173-5882
Jacquin C NilesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.ORCID 0000-0002-6250-8796
Taco W A Kooij *Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. taco.kooij@radboudumc.nl.ORCID 0000-0002-8547-7523
Koen J Dechering *TropIQ Health Sciences, Nijmegen, The Netherlands. k.dechering@tropiq.nl.ORCID 0000-0002-8124-4634
Medicines for Malaria Venture · CHTropIQ Health Sciences · NLRadboud University Nijmegen · NLColumbia University Irving Medical Center · USGlaxoSmithKline (Spain) · ESImperial College London · GBInstitut Pasteur du Cambodge · KHMassachusetts Institute of Technology · USPennsylvania State University · USUniversidade Federal de São Carlos · BRDominican University of California · USHarvard University · USInfectious Diseases Research Collaboration · UGJeroen Bosch Ziekenhuis · NLSwiss Tropical and Public Health Institute · CHUniversity of California, San Francisco · USUniversity of Colorado Anschutz Medical Campus · US
Funding
Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipelineR01AI139179 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Philip Jon Rosenthal · 2018 to 2026
$6.3MDefining P. falciparum resistance to artemisinin-based combination therapiesR01AI109023 · NIAID · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI FIDOCK, DAVID A · 2014 to 2025
$4.4MIntegrative Analysis of Metabolic Phenotypes (IAMP) Predoctoral Training ProgramT32DK120509 · NIDDK · PENNSYLVANIA STATE UNIVERSITY, THE · PI PATTERSON, ANDREW, PERDEW, GARY H. · 2020 to 2024
$781kNIAID NIH HHS R01 AI109023NIAID NIH HHS R01 AI139179NIDDK NIH HHS T32 DK120509Wellcome TrustWellcome Trust 100993/Z/13/Z
Abstract
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.
Indexed as
AntimalarialsFolic Acid AntagonistsMalariaMalaria, FalciparumMalaria, VivaxAnimalsMicePantothenic AcidPlasmodium falciparumRatsAntimalarialsFolic Acid AntagonistspantothenamidePantothenic Acid
Identifiers
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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 Socratic graph.