Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection - Archive ouverte HAL Access content directly
Journal Articles Sci Transl Med Year : 2019

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

(1) , (1) , (2) , (2) , (3) , (2) , (1, 4) , (4)
1
2
3
4

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 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.
Embargoed file
Embargoed file
Ne sera jamais visible
Loading...

Dates and versions

inserm-02440382 , version 1 (15-01-2020)

Identifiers

Cite

Christopher Swale, Alexandre Bougdour, Audrey Gnahoui-David, Julie Tottey, Sonia Georgeault, et al.. Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection. Sci Transl Med, 2019, 11 (517), 11 p. ⟨10.1126/scitranslmed.aax7161⟩. ⟨inserm-02440382⟩
116 View
1 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More