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

Abstract

Session : Vaccination, chemotherapy and controlInternational audienceCryptosporidium parvum is one of the most important diseases of young ruminant livestock, particularly neonatal calves. Infected animals may suffer from profuse watery diarrhoea, dehydration and in severe cases death can occur. Chemotherapy is very limited and there is a need for more effective treatments. Here we show inhibition of cleavage and polyadenylation specificity factor 3 (CPSF3) as a new strategy to control Cryptosporidium infection. Remarkably, we find that oxaborole-mediated inhibition of CPSF3 reduces intestinal parasite burden in both immunocompromised and neonatal mouse models with far better efficacy than nitazoxanide. We present crystal structures (1.6 to 2.0 Å) revealing an unprecedented mechanism of action, whereby the mRNA processing activity of CPSF3 is efficiently blocked by the binding of the oxaborole group at the metal-dependent catalytic center. Our data provide insights to accelerate the development of next-generation anti-Cryptosporidium therapeutics. Given the high structural similarity of the CPSF3 drug site of other parasites, it is very likely that the CPSF3 inhibition mechanism proposed here is shared across parasite species, such as Plasmodium, Toxoplasma and trypanosomatids