Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum - Institut Pasteur Accéder directement au contenu
Article Dans Une Revue iScience Année : 2023

Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum

Résumé

Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus that are active against Plasmodium falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35 to 88 nM). Chemical optimization led to compound 125 with significantly improved preclinical properties. 125 delays the onset of parasitemia in Plasmodium berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays), and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy, we characterized the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that are not targeted by the actual antimalarial drugs or implicated in drug-resistance mechanisms.
Fichier principal
Vignette du fichier
main.pdf (2.73 Mo) Télécharger le fichier
1-s2.0-S2589004223000172-mmc1.pdf (254.71 Ko) Télécharger le fichier
1-s2.0-S2589004223000172-mmc2.pdf (487.92 Ko) Télécharger le fichier
1-s2.0-S2589004223000172-mmc3.pdf (546.82 Ko) Télécharger le fichier
1-s2.0-S2589004223000172-mmc4.pdf (522.8 Ko) Télécharger le fichier
Origine : Publication financée par une institution
Licence : CC BY NC ND - Paternité - Pas d'utilisation commerciale - Pas de modification
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

pasteur-04099097 , version 1 (16-05-2023)

Licence

Paternité - Pas d'utilisation commerciale - Pas de modification

Identifiants

Citer

Flore Nardella, Irina Dobrescu, Haitham Hassan, Fabien Rodrigues, Sabine Thiberge, et al.. Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum. iScience, 2023, 26 (2), pp.105940. ⟨10.1016/j.isci.2023.105940⟩. ⟨pasteur-04099097⟩
32 Consultations
44 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More