期刊
EMBO MOLECULAR MEDICINE
卷 9, 期 3, 页码 385-394出版社
WILEY
DOI: 10.15252/emmm.201607370
关键词
benzoxaborole; CPSF3; drug discovery; mRNA processing; Toxoplasma gondii; toxoplasmosis
资金
- Laboratoire d'Excellence (LabEx) ParaFrap [ANR-11-LABX-0024]
- European Research Council [ERC] [614880]
- grant ANR Blanc TOXOHDAC [ANR-12-BSV3-0009-01]
- grant ANR Jeune Chercheur ToxoEffect [ANR-12-JSV3-0004-01]
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV3-0009, ANR-12-JSV3-0004] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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