Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 04 2022
20 04 2022
Historique:
received:
17
05
2021
accepted:
09
03
2022
entrez:
21
4
2022
pubmed:
22
4
2022
medline:
23
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35444200
doi: 10.1038/s41467-022-29688-5
pii: 10.1038/s41467-022-29688-5
pmc: PMC9021288
doi:
Substances chimiques
Antimalarials
0
Folic Acid Antagonists
0
Pantothenic Acid
19F5HK2737
pantothenamide
2MO0ZY19DW
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2158Subventions
Organisme : NIAID NIH HHS
ID : R01 AI109023
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI139179
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK120509
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100993/Z/13/Z
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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