Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183
-
Published:2022-04-20
Issue:1
Volume:13
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
de Vries Laura E.ORCID, Jansen Patrick A. M., Barcelo Catalina, Munro Justin, Verhoef Julie M. J.ORCID, Pasaje Charisse Flerida A.ORCID, Rubiano Kelly, Striepen JosefineORCID, Abla Nada, Berning LuukORCID, Bolscher Judith M., Demarta-Gatsi ClaudiaORCID, Henderson Rob W. M., Huijs Tonnie, Koolen Karin M. J., Tumwebaze Patrick K., Yeo TomasORCID, Aguiar Anna C. C., Angulo-Barturen IñigoORCID, Churchyard AlisjeORCID, Baum JakeORCID, Fernández Benigno Crespo, Fuchs Aline, Gamo Francisco-Javier, Guido Rafael V. C.ORCID, Jiménez-Diaz María Belén, Pereira Dhelio B.ORCID, Rochford Rosemary, Roesch CamilleORCID, Sanz Laura M.ORCID, Trevitt Graham, Witkowski Benoit, Wittlin Sergio, Cooper Roland A., Rosenthal Philip J., Sauerwein Robert W., Schalkwijk JoostORCID, Hermkens Pedro H. H., Bonnert Roger V., Campo BriceORCID, Fidock David A.ORCID, Llinás ManuelORCID, Niles Jacquin C.ORCID, Kooij Taco W. A.ORCID, Dechering Koen J.ORCID
Abstract
AbstractDrug 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.
Funder
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference78 articles.
1. WHO. World Malaria Report 2020. 2020. 2. Blasco, B., Leroy, D. & Fidock, D. A. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nat. Med. 23, 917–928. (2017). 3. Conrad, M. D. & Rosenthal, P. J. Antimalarial drug resistance in Africa: the calm before the storm? Lancet Infect. Dis. 19, e338–e51. (2019). 4. Burrows, J. N. et al. New developments in anti-malarial target candidate and product profiles. Malar. J. 16, 26 (2017). 5. Leonardi, R., Zhang, Y. M., Rock, C. O. & Jackowski, S. Coenzyme A: back in action. Prog. Lipid Res. 44, 125–153. (2005).
Cited by
16 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|