Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity.
Cell Chem Biol
; 27(7): 806-816.e8, 2020 07 16.
Article
em En
| MEDLINE
| ID: mdl-32359426
ABSTRACT
The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084. PKG is known to play essential roles in Plasmodium invasion of and egress from host cells, matching MMV030084's activity profile. Resistance selections and gene editing identified tyrosine kinase-like protein 3 as a low-level resistance mediator for PKG inhibitors, while PKG itself never mutated under pressure. These studies highlight PKG as a resistance-refractory antimalarial target throughout the Plasmodium life cycle and promote MMV030084 as a promising Plasmodium PKG-targeting chemotype.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Resistência a Medicamentos
/
Proteínas de Protozoários
/
Proteínas Quinases Dependentes de GMP Cíclico
/
Antimaláricos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Cell Chem Biol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos