Format

Send to

Choose Destination
EMBO Mol Med. 2017 Mar;9(3):385-394. doi: 10.15252/emmm.201607370.

Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis.

Author information

1
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France andres.palencia@univ-grenoble-alpes.fr alexandre.bougdour@univ-grenoble-alpes.fr mohamed-ali.hakimi@univ-grenoble-alpes.fr.
2
European Molecular Biology Laboratory (EMBL), Grenoble Outstation and Unit of Virus Host-Cell Interactions, University of Grenoble-EMBL-Centre National de la Recherche Scientifique, Grenoble Cedex 9, France.
3
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
4
Institute for Advanced Biosciences (IAB), OPTIMAL Small Animal Imaging Facility, Grenoble, France.
5
Anacor Pharmaceuticals Inc., Palo Alto, CA, USA.
6
Department of Medicine, University of California, San Francisco, CA, USA.

Abstract

Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment discontinuation. Here we report that the benzoxaborole AN3661 had potent in vitro activity against T. gondii Parasites selected to be resistant to AN3661 had mutations in TgCPSF3, which encodes a homologue of cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3), an endonuclease involved in mRNA processing in eukaryotes. Point mutations in TgCPSF3 introduced into wild-type parasites using the CRISPR/Cas9 system recapitulated the resistance phenotype. Importantly, mice infected with T. gondii and treated orally with AN3661 did not develop any apparent illness, while untreated controls had lethal infections. Therefore, TgCPSF3 is a promising novel target of T. gondii that provides an opportunity for the development of anti-parasitic drugs.

KEYWORDS:

Toxoplasma gondii ; CPSF3; benzoxaborole; drug discovery; mRNA processing; toxoplasmosis

PMID:
28148555
PMCID:
PMC5331205
DOI:
10.15252/emmm.201607370
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center