| Full text | |
| Author(s): Show less - |
de Vries, Laura E.
;
Jansen, Patrick A. M.
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Barcelo, Catalina
;
Munro, Justin
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Verhoef, Julie M. J.
;
Pasaje, Charisse Flerida A.
;
Rubiano, Kelly
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Striepen, Josefine
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Abla, Nada
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Berning, Luuk
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Bolscher, Judith M.
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Demarta-Gatsi, Claudia
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Henderson, Rob W. M.
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Huijs, Tonnie
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Koolen, Karin M. J.
;
Tumwebaze, Patrick K.
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Yeo, Tomas
;
Aguiar, Anna C. C.
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Angulo-Barturen, Inigo
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Churchyard, Alisje
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Baum, Jake
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Fernandez, Benigno Crespo
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Fuchs, Aline
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Gamo, Francisco-Javier
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Guido, Rafael V. C.
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Jimenez-Diaz, Maria Belen
;
Pereira, Dhelio B.
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Rochford, Rosemary
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Roesch, Camille
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Sanz, Laura M.
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Trevitt, Graham
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Witkowski, Benoit
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Wittlin, Sergio
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Cooper, Roland A.
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Rosenthal, Philip J.
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Sauerwein, Robert W.
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Schalkwijk, Joost
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Hermkens, Pedro H. H.
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Bonnert, Roger, V
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Campo, Brice
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Fidock, David A.
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Llinas, Manuel
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Niles, Jacquin C.
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Kooij, Taco W. A.
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Dechering, Koen J.
Total Authors: 45
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| Document type: | Journal article |
| Source: | NATURE COMMUNICATIONS; v. 13, n. 1, p. 16-pg., 2022-04-20. |
| 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. (AU) | |
| FAPESP's process: | 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery |
| Grantee: | Glaucius Oliva |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |
| FAPESP's process: | 19/19708-0 - Identification of new antimalarial compounds: a multidisciplinary strategy aimed to search for potent chemical classes against new molecular targets and different stages of life of Plasmodium spp |
| Grantee: | Anna Caroline Campos Aguiar |
| Support Opportunities: | Research Grants - Young Investigators Grants |
| FAPESP's process: | 20/12904-5 - Discovery of Plasmodium falciparum inhibitors from Cerrado plants as lead compounds candidates for malaria: integrated studies of ultra-efficient chromatography, spectroscopy, and biological assays |
| Grantee: | Rafael Victorio Carvalho Guido |
| Support Opportunities: | BIOTA-FAPESP Program - Regular Research Grants |