Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection
2019
Swale, Christopher | Bougdour, Alexandre | Gnahoui-David, Audrey | Tottey, Julie | Georgeault, Sonia | Laurent, Fabrice | Palencia, Andrés | Hakimi, Mohamed-Ali | Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) ; Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]) | Infectiologie et Santé Publique (UMR ISP) ; Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT) | Plateforme IBISA de Microscopie Electronique [CHRU de Tours] (PFME-Tours) ; Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT) | Host-Pathogen Interactions and Immunity to Infection [Grenoble] ; Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) ; Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA) | French National Research Agency (ANR) (RC18114CC) ; FINOVI (RC17039CC) ; IDEX-IRS program of the University of Grenoble Alpes 7C043IAB) ; INRA young researcher starting grant | ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011) | European Project: 614880,EC:FP7:ERC,ERC-2013-CoG,HOSTINGTOXO(2014) | European Project: 653706,H2020,H2020-INFRAIA-2014-2015,iNEXT(2015)
International audience
Mostrar más [+] Menos [-]Inglés. Cryptosporidium is an intestinal pathogen that causes severe but self-limiting diarrhea in healthy humans, yet it can turn into a life-threatening, unrelenting infection in immunocompromised patients and young children. Severe diarrhea is recognized as the leading cause of mortality for children below 5 years of age in developing countries. The only approved treatment against cryptosporidiosis, nitazoxanide, has limited efficacy in the most vulnerable patient populations, including malnourished children, and is ineffective in immunocompromised individuals. Here, we investigate inhibition of the parasitic cleavage and polyadenylation specificity factor 3 (CPSF3) as a strategy to control Cryptosporidium infection. We show that the oxaborole AN3661 selectively blocked Cryptosporidium growth in human HCT-8 cells, and oral treatment with AN3661 reduced intestinal parasite burden in both immuno-compromised and neonatal mouse models of infection with greater efficacy than nitazoxanide. Furthermore, we present crystal structures of recombinantly produced Cryptosporidium CPSF3, revealing a mechanism of action whereby the mRNA processing activity of this enzyme is efficiently blocked by the binding of the oxaborole group at the metal-dependent catalytic center. Our data provide insights that may help accelerate the development of next-generation anti-Cryptosporidium therapeutics.
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