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Sci Transl Med. 2019 Nov 6;11(517). pii: eaax7161. doi: 10.1126/scitranslmed.aax7161.

Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection.

Author information

1
Institute for Advanced Biosciences (IAB), Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR 5309, University Grenoble Alpes, 38000 Grenoble, France.
2
INRA, Université François Rabelais de Tours, Centre Val de Loire, UMR1282 ISP, Laboratoire Apicomplexes et Immunité Mucosale, 37380 Nouzilly, France.
3
Plateforme des Microscopies, Université et CHRU de Tours, 37000 Tours, France.
4
INRA, Université François Rabelais de Tours, Centre Val de Loire, UMR1282 ISP, Laboratoire Apicomplexes et Immunité Mucosale, 37380 Nouzilly, France. mohamed-ali.hakimi@inserm.fr andres.palencia@univ-grenoble-alpes.fr fabrice.laurent@inra.fr.
5
Institute for Advanced Biosciences (IAB), Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR 5309, University Grenoble Alpes, 38000 Grenoble, France. mohamed-ali.hakimi@inserm.fr andres.palencia@univ-grenoble-alpes.fr fabrice.laurent@inra.fr.
6
Institute for Advanced Biosciences (IAB), Structural Biology of Novel Drug Targets in Human Diseases, INSERM U1209, CNRS UMR 5309, University Grenoble Alpes, 38000 Grenoble, France.

Abstract

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 immunocompromised 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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