EMBO Mol Med. 2017 Feb 1. pii: e201607370. doi: 10.15252/emmm.201607370. [Epub ahead of print]
Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis
Palencia A1,2,
Bougdour A1,
Brenier-Pinchart MP3,
Touquet B3,
Bertini RL3,
Sensi C2,
Gay G3,
Vollaire J4,
Josserand V4,
Easom E5,
Freund YR5,
Pelloux H3,
Rosenthal PJ6,
Cusack S2,
Hakimi MA1.
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.
© 2017 The Authors. Published under the terms of the CC BY 4.0 license.
KEYWORDS:
Toxoplasma gondii ; CPSF3; benzoxaborole; drug discovery; mRNA processing; toxoplasmosis
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