دورية أكاديمية
Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183
| العنوان: | Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183 |
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| المؤلفون: | de Vries, Laura, E, Jansen, Patrick, a M, Barcelo, Catalina, Munro, Justin, Verhoef, Julie, M J, Pasaje, Charisse, Flerida A, Rubiano, Kelly, Striepen, Josefine, Abla, Nada, Berning, Luuk, Bolscher, Judith, M, Demarta-Gatsi, Claudia, Henderson, Rob, W M, Huijs, Tonnie, Koolen, Karin, M J, Tumwebaze, Patrick, K, Yeo, Tomas, Aguiar, Anna, C C, Angulo-Barturen, Iñigo, Churchyard, Alisje, Baum, Jake, Fernández, Benigno, Crespo, Fuchs, Aline, Gamo, Francisco-Javier, Guido, Rafael, V C, Jiménez-Diaz, María, Belén, Pereira, Dhelio, B, Rochford, Rosemary, Roesch, Camille, Sanz, Laura, M, Trevitt, Graham, Witkowski, Benoît, Wittlin, Sergio, Cooper, Roland, A, Rosenthal, Philip, J, Sauerwein, Robert, W, Schalkwijk, Joost, Hermkens, Pedro, H H, Bonnert, Roger, V, Campo, Brice, Fidock, David, A, Llinás, Manuel, Niles, Jacquin, C, Kooij, Taco, W A, Dechering, Koen, J |
| المساهمون: | Radboud University Medical Center Nijmegen, Medicines for Malaria Venture Geneva (MMV), Pennsylvania State University (Penn State), Penn State System, Massachusetts Institute of Technology (MIT), Columbia University Irving Medical Center (CUIMC), Infectious Diseases Research Collaboration Kampala, Ouganda, Universidade de São Paulo = University of São Paulo (USP), The Art of Discovery Bizkaia, Spain (TAD), Imperial College London, GlaxoSmithKline, Glaxo Smith Kline, Malaria Translational Research Unit (MTRU), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur Paris (IP)-Université Paris Cité (UPCité), TropIQ Health Sciences Nijmegen, The Netherlands |
| المصدر: | ISSN: 2041-1723. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | [SDV]Life Sciences [q-bio] |
| الوصف: | International audience ; 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/35444200; pasteur-03699217; https://pasteur.hal.science/pasteur-03699217Test; https://pasteur.hal.science/pasteur-03699217/documentTest; https://pasteur.hal.science/pasteur-03699217/file/deVries_natCom.pdfTest; PUBMED: 35444200; PUBMEDCENTRAL: PMC9021288 |
| DOI: | 10.1038/s41467-022-29688-5 |
| الإتاحة: | https://doi.org/10.1038/s41467-022-29688-5Test https://pasteur.hal.science/pasteur-03699217Test https://pasteur.hal.science/pasteur-03699217/documentTest https://pasteur.hal.science/pasteur-03699217/file/deVries_natCom.pdfTest |
| حقوق: | http://creativecommons.org/licenses/byTest/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.41CBD562 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-022-29688-5 |
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